Methods of inducing anesthesia

ABSTRACT

The present invention provides methods for determining the selectivity of an anesthetic for an anesthetic-sensitive receptor by determining the molar water solubility of the anesthetic. The invention further provides methods for modulating the selectivity of an anesthetic for an anesthetic-sensitive receptor by altering or modifying the anesthetic to have higher or lower water solubility. The invention further provides methods of inducing anesthesia in a subject by administering via the respiratory pathways (e.g., via inhalational or pulmonary delivery) an effective amount of an anesthetic compound identified according to the present methods.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 15/986,656, filed May 22, 2018, which is a continuation of U.S.patent application Ser. No. 15/788,034, filed Oct. 19, 2017 (now U.S.Pat. No. 10,010,525), which is a continuation of U.S. patent applicationSer. No. 13/830,907, filed Mar. 14, 2013, which claims the benefit ofU.S. Provisional Patent Application No. 61/681,747, filed Aug. 10, 2012,and of U.S. Provisional Patent Application No. 61/670,098, filed Jul.10, 2012, which applications are incorporated herein by reference intheir entirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

This invention was made with government support under Grant No. GM092821awarded by National Institutes of Health. The government has certainrights in the invention.

FIELD OF THE INVENTION

The present invention provides methods for determining the selectivityof an anesthetic for an anesthetic-sensitive receptor by determining themolar water solubility of the anesthetic. The invention further providesmethods for modulating the selectivity of an anesthetic for ananesthetic-sensitive receptor by altering or modifying the anesthetic tohave higher or lower water solubility. The invention further providesmethods of inducing anesthesia in a subject by administering via therespiratory pathways (e.g., via inhalational or pulmonary delivery) aneffective amount of an anesthetic compound identified according to thepresent methods.

BACKGROUND OF THE INVENTION

Molecular Mechanisms of Anesthetic Action

All general anesthetics in common clinical use modulate eitherthree-transmembrane (TM3) ion channels (e.g., NMDA receptors),four-transmembrane (TM4) ion channels (e.g., GABA_(A) receptors), ormembers of both ion channel superfamilies. Sonner, et al., Anesth Analg(2003) 97:718-40. For example, many structurally unrelated inhaledanesthetics potentiate GABA_(A) currents and inhibit NMDA currents. Butwhy should a diverse group of compounds all modulate unrelated ionchannels? A highly specific “induced fit” model between protein andligand, as proposed for enzyme-substrate binding, (Koshland, Proc NatlAcad Sci USA 1958; 44: 98-104) is problematic since it implies theconservation of specific binding sites across non-homologous proteins tocompounds (i.e., anesthetics) not found in nature. Sonner, Anesth Analg(2008) 107: 849-54. Moreover, promiscuous anesthetic actions ondisparate receptors typically occurs at drug concentrations 50-200 timesthe median effective concentration (EC50) at which modulation of asingle receptor class typically occurs, such as with etomidate agonismof GABA_(A) receptors (Tomlin et al., Anesthesiology (1998) 88: 708-17;Hill-Venning, et al., Br J Pharmacol (1997) 120: 749-56; Belelli, etal., Br J Pharmacol (1996) 118: 563-76; Quast, et al., J Neurochem(1983) 41:418-25; and Franks, Br J Pharmacol 2006; 147 Suppl 1: S72-81)or dizocilpine (MK-801) antagonism of NMDA receptors. Wong, et al., ProcNatl Acad Sci USA (1986) 83: 7104-8; Ransom, et al., Brain Res (1988)444: 25-32; and Sircar, et al., Brain Res (1987) 435: 235-40. It isunknown what molecular properties confer specificity for a singlereceptor (or members of a single receptor superfamily) and whatproperties allow other anesthetics to modulate multiple unrelatedreceptors. However, since ion channel modulation is important toconferring desirable anesthetic efficacy—as well as undesirable drugside effects—it is desirable to know what factors influence anestheticreceptor specificity in order to develop new and safer agents.

Anesthetics and Specific Ion Channel Targets

General anesthetics mediate central nervous system depression throughactions on cell membrane receptors and channels which have a nethyperpolarizing effect on neurons. Sonner, et al., Anesth Analg (2003)97:718-40; Grasshoff, et al., Eur J Anaesthesiol (2005) 22: 467-70;Franks, Br J Pharmacol (2006) 147 Suppl 1: S72-81; 33; Hemmings, et al.,Trends Pharmacol Sci (2005) 26: 503-10; and Forman, et al., IntAnesthesiol Clin (2008) 46: 43-53. Although anesthetics partition intocell membranes as a function of lipid solubility, it is throughcompetitive protein binding that these agents most likely produceanesthetic effects. In fact, general anesthetics have been shown tocompetitively inhibit functions of membrane-free enzymes (Franks, etal., Nature (1984) 310: 599-601), indicating that the lipid phase is notessential for anesthetic modulation of protein function. Specifichigh-affinity binding sites have been identified for some of theseanesthetics. For example, propofol (Jewett, et al., Anesthesiology(1992) 77: 1148-54; Bieda, et al., J Neurophysiol (2004) 92: 1658-67;Peduto, et al., Anesthesiology 1991; 75: 1000-9; Sonner, et al, AnesthAnalg (2003) 96: 706-12; and Dong et al., Anesth Analg (2002) 95:907-14), etomidate (Flood, et al., Anesthesiology (2000) 92: 1418-25;Zhong, et al., Anesthesiology 2008; 108: 103-12; O'Meara, et al.,Neuroreport (2004) 15: 1653-6), and thiopental (Jewett, et al.,Anesthesiology (1992) 77: 1148-54; Bieda, et al, J Neurophysiol (2004)92: 1658-67; Yang, et al., Anesth Analg (2006) 102: 1114-20) allpotently potentiate GABA_(A) receptor currents, and their anestheticeffects are potently antagonized or prevented by GABA_(A) receptorantagonists, such as pictotoxin or bicuculline. Ketamine producesanesthesia largely (but not entirely) through its antagonism of NMDAreceptors. Harrison et al., Br J Pharmacol (1985) 84: 381-91; Yamamura,et al., Anesthesiology (1990) 72: 704-10; and Kelland, et al., PhysiolBehav (1993) 54: 547-54. Dexmedetomidine is a specific α2 adrenoreceptoragonist that is antagonized by specific α2 adrenoreceptor antagonists,such as atipamezole. Doze, et al., Anesthesiology (1989) 71: 75-9;Karhuvaara, et al., Br J Clin Pharmacol (1991) 31: 160-5; andCorrea-Sales, et al., Anesthesiology (1992) 76: 948-52. It is probablynot by coincidence that anesthetics for which a single receptorcontributes to most or all of the anesthetic effect also have lowaqueous ED50 values (see, Table 1).

TABLE 1 Aqueous phase EC50 for several anesthetics. Aqueous AnestheticEC₅₀ (μM) Species Reference Propofol 2 Rat Tonner et al., Anesthesiology(1992) 77: 926-31 Ketamine 2 Human Flood, et al., Anesthesiology (2000)92: 1418-25 Etomidate 3 Tadpole Tomlin, et al., Anesthesiology (1998)88: 708-17 Dexmedetomidine 7 Tadpole Tonner, et al., Anesth Analg (1997)84: 618-22 Thiopental 25 Human Flood, et al., Anesthesiology (2000) 92:1418-25 Methoxyflurane 210 Tadpole Franks, et al., Br J Anaesth (1993)71: 65-76 Halothane 230 Tadpole Franks, et al., Br J Anaesth (1993) 71:65-76 Isoflurane 290 Tadpole Franks, et al., Br J Anaesth (1993) 71:65-76 Chloroform 1300 Tadpole Franks, et al., Br J Anaesth (1993) 71:65-76 Diethyl ether 25000 Tadpole Franks, et al., Br J Anaesth (1993)71: 65-76

Ion channel mutations, either in vitro or in vivo, dramatically alteranesthetic sensitivity, not only for the very potent and specificagents, but also for the inhaled anesthetics. Several mutations in theGABA_(A) (Hara, et al., Anesthesiology 2002; 97: 1512-20; Jenkins, etal., J Neurosci 2001; 21: RC136; Krasowski, et al., Mol Pharmacol 1998;53: 530-8; Scheller, et al., Anesthesiology 2001; 95: 123-31; Nishikawa,et al., Neuropharmacology 2002; 42: 337-45; Jenkins, et al.,Neuropharmacology 2002; 43: 669-78; Jurd, et al., FASEB J 2003; 17:250-2; Kash, et al., Brain Res 2003; 960: 36-41; Borghese, et al., JPharmacol Exp Ther 2006; 319: 208-18; Drexler, et al., Anesthesiology2006; 105: 297-304) or NMDA (Ogata, et al., J Pharmacol Exp Ther (2006)318: 434-43; Dickinson, et al., Anesthesiology 2007; 107: 756-67)receptor can decrease responses to isoflurane, halothane, and othervolatile anesthetics. Although mutations that render receptorsinsensitive to anesthetics could suggest a single site that isresponsible for binding a specific drug, it need not be the case. Mostof these mutations are believed to reside near lipid-water interfaces,either in amphiphilic protein pockets (Bertaccini et al., Anesth Analg(2007) 104: 318-24; Franks, et al., Nat Rev Neurosci (2008) 9: 370-86)or near the outer lipid membrane. It is possible that an anestheticcould be excluded from its protein interaction site because of size.However, it is also possible that the mutation substantially increases(but does not entirely exclude) the number of “non-specific”low-affinity anesthetic-protein interactions necessary to modulate thereceptor. In this case, modulation of the mutant receptor will eitheronly occur at anesthetic concentrations in excess of the wild-typeminimum alveolar concentration (MAC) (Eger, et al., Anesthesiology(1965) 26: 756-63) or, if the drug is insufficiently soluble at theactive site to allow a sufficient number of “non-specific” interactionswith the mutant protein, no receptor modulation will be possible even atsaturating aqueous drug concentrations.

Another argument for specific “induced fit” binding sites on ionchannels is the “cut-off” effect. For example, increasing the carbonchain length of an alkanol increases lipid solubility and anestheticpotency, as predicted by the Meyer-Overton hypothesis (Overton C E:Studies of Narcosis. London, Chapman and Hall, 1991), until a 12-carbonchain length (dodecanol) is reached (Alifimoff, et al., Br J Pharmacol(1989) 96: 9-16). Alkanols with a longer chain length were notanesthetics (hence, a “cut-off” effect at C=13 carbons). However, thehydrocarbon chain length needed to reach the cut-off effect is C=9 foralkanes (Liu, et al., Anesth Analg (1993) 77: 12-8), C=2 forperfluorinated alkanes (Liu, et al., Anesth Analg (1994) 79: 238-44),and C=3 for perfluorinated methyl ethyl ethers (Koblin, et al., AnesthAnalg (1999) 88: 1161-7). If size is essential to access a specificanesthetic binding site, then why is the “cut-off” chain length notconstant? At the cellular level, straight-chain alcohols can maximallyinhibit NMDA receptor function up to octanol with complete cut-off atC=10. But straight-chain 1, Ω-diols maximally inhibit NMDA receptors upto decanol, with complete cut-off not observed until C=16 (Peoples, etal., Mol Pharmacol (2002) 61: 169-76). Increasing hydrocarbon chainlength does not only increase molecular volume, but also decreases watersolubility. The cut-off effect therefore refers to a minimum watersolubility necessary to produce an effect, rather than a maximummolecular size.

Anesthetics and low-affinity “non-specific” ion channel effects

At the tens of micromolar concentrations or less, anesthetics mostlikely exert their effects on ion channels by specific binding torelatively high-affinity sites on proteins to induce a conformationalchange that alters ion conductance, either alone or in the presence ofanother endogenous ligand. However, these agents can still interact withother receptors (or the same receptor at different sites) if present inhigher concentrations. For example, assume that two dissimilar receptors(R1 and R2) each can exert an anesthetic effect. Assuming that efficacyof a drug at R1=1, that R1 is able to produce a full anesthetic effectin isolation, and that the EC99 of R1 is less than the EC1 of R2, thenthis drug will produce anesthesia by selectively modulating R1. However,if any of these assumptions is not true, then some contribution of R2will be required to produce an anesthetic effect (FIG. 1).

Many injectable anesthetics seem to follow the example described above.Propofol is a positive modulator of GABA_(A) receptor currents with anEC50 around 60 μM (Hill-Venning, et al., Br J Pharmacol (1997) 120:749-56; Prince, et al., Biochem Pharmacol (1992) 44: 1297-302; Orser, etal., J Neurosci (1994) 14: 7747-60; Reynolds, et al., Eur J Pharmacol(1996) 314: 151-6), and propofol is believed to mediate the majority ofits anesthetic effects through potentiation of GABA_(A) currents(Sonner, et al, Anesth Analg (2003) 96: 706-12). However, propofol alsoinhibits currents from the unrelated NMDA receptor with an IC50 of 160μM (Orser, et al., Br J Pharmacol (1995) 116: 1761-8). Ketamine producesanesthesia largely through antagonism of NMDA receptors, which itinhibits with an IC50 of 14 μM (Liu, et al., Anesth Analg (2001) 92:1173-81), although 365 μM ketamine also increases unrelated 4transmembrane GABA_(A) receptor currents by 56% (Lin, et al., JPharmacol Exp Ther (1992) 263: 569-78). In these cases, it seemsplausible that 2 different types of interactions (for high- vs.low-affinity responses) could occur on a single receptor to produce thesame qualitative effect. In contrast, volatile inhaled anestheticsgenerally have little or no effect on GABA_(A) and NMDA receptors ataqueous phase concentrations <50 μM (Lin, et al., J Pharmacol Exp Ther(1992) 263: 569-78; Moody, et al., Brain Res (1993) 615: 101-6; Harris,et al., J Pharmacol Exp Ther (1993) 265: 1392-8; Jones, et al., JPhysiol (1992) 449: 279-93; Hall, et al., Br J Pharmacol (1994) 112:906-10). It is possible that these agents are not specific ligands forany anesthetic-sensitive receptor that is relevant to immobility; thusthey may rely only on nonspecific protein-ligand interactions that, inturn, may be reflected in the higher aqueous phase concentrations ofthese agents required for anesthesia (Table 1).

BRIEF SUMMARY OF THE INVENTION

In one aspect, the invention provides methods of inducing anesthesia ina subject. In some embodiments, the methods comprise administering tothe subject via the respiratory system an effective amount of a compoundor a mixture of compounds of Formula I:

-   -   wherein:    -   n is 0-4,    -   R¹ is H;    -   R², R³, R⁴, R⁵ and R⁶ independently are selected from H, X, CX₃,        CHX₂, CH₂X and C₂X₅; and    -   wherein X is a halogen, the compound having vapor pressure of at        least 0.1 atmospheres (76 mmHg) at 25° C., and the number of        hydrogen atoms in Formula I do not exceed the number of carbon        atoms, thereby inducing anesthesia in the subject. In various        embodiments, X is a halogen selected from the group consisting        of F, Cl, Br and I. In some embodiments, X is F. In some        embodiments, le is selected from H, CHFOH, CHFOH and CF₂OH,        CHClOH, CCl₂OH and CFClOH. In some embodiments, R², R³, R⁴, R⁵        and R⁶ independently are selected from H, F, Cl, Br, I, CF₃,        CHF₂, CH₂F, C₂F₅, CCl₃, CHCl₂, CH₂Cl, C₂Cl₅, CCl₂F, CClF₂,        CHClF, C₂ClF₄, C₂Cl₂F₃, C₂Cl₃F₂, and C₂Cl₄F. In some        embodiments, the compound is selected from the group consisting        of:

-   a) Methanol, 1-fluoro-1-[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]-    (CAS #1351959-82-4);

-   b) 1-Butanol, 4,4,4-trifluoro-3,3-bis(trifluoromethyl)- (CAS    #14115-49-2);

-   c) 1-Butanol, 1,1,2,2,3,3,4,4,4-nonafluoro- (CAS #3056-01-7);

-   d) 1-Butanol, 2,2,3,4,4,4-hexafluoro-3-(trifluoromethyl)- (CAS    #782390-93-6);

-   e) 1-Butanol, 3,4,4,4-tetrafluoro-3-(trifluoromethyl)- (CAS    #90999-87-4);

-   f) 1-Pentanol, 1,1,4,4,5,5,5-heptafluoro- (CAS #313503-66-1); and

-   g) 1-Pentanol, 1,1,2,2,3,3,4,4,5,5,5-undecafluoro- (CAS    #57911-98-5).

In a further aspect, the invention provides methods of inducinganesthesia in a subject. In some embodiments, the methods compriseadministering to the subject via the respiratory system an effectiveamount of a compound or a mixture of compounds of Formula II:

-   -   wherein:    -   n is 1-3,    -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ independently are selected        from H, X, CX₃, CHX₂, CH₂X and C₂X₅; and    -   wherein X is a halogen, the compound having vapor pressure of at        least 0.1 atmospheres (76 mmHg) at 25° C., and the number of        hydrogen atoms in Formula II do not exceed the number of carbon        atoms, thereby inducing anesthesia in the subject. In various        embodiments, X is a halogen selected from the group consisting        of F, Cl, Br and I. In some embodiments, X is F. In some        embodiments, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ independently are        selected from H, F, Cl, Br, I, CF₃, CHF₂, CH₂F, C₂F₅, CCl₃,        CHCl₂, CH₂Cl, C₂Cl₅, CCl₂F, CClF₂, CHClF, C₂ClF₄, C₂Cl₂F₃,        C₂Cl₃F₂, and C₂Cl₄F. In some embodiments, the compound is        selected from the group consisting of:

-   a) Ethane, 1,1,2-trifluoro-1,2-bis(trifluoromethoxy)- (CAS    #362631-92-3);

-   b) Ethane, 1,1,1,2-tetrafluoro-2,2-bis(trifluoromethoxy)- (CAS    #115395-39-6);

-   c) Ethane,    1-(difluoromethoxy)-1,1,2,2-tetrafluoro-2-(trifluoromethoxy)- (CAS    #40891-98-3);

-   d) Ethane, 1,1,2,2-tetrafluoro-1,2-bis(trifluoromethoxy)- (CAS    #378-11-0);

-   e) Ethane, 1,2-difluoro-1,2-bis(trifluoromethoxy)- (CAS    #362631-95-6);

-   f) Ethane, 2-bis(trifluoromethoxy)- (CAS #1683-90-5);

-   g) Propane, 1,1,3,3-tetrafluoro-1,3-bis(trifluoromethoxy)- (CAS    #870715-97-2);

-   h) Propane, 2,2-difluoro-1,3-bis(trifluoromethoxy)- (CAS    #156833-18-0);

-   i) Propane, 1,1,1,3,3-pentafluoro-3-methoxy-2-(trifluoromethoxy)-    (CAS #133640-19-4;

-   j) Propane, 1,1,1,3,3,3-hexafluoro-2-(fluoromethoxymethoxy)- (CAS    #124992-92-3); and

-   k) Propane, 1,1,1,2,3,3-hexafluoro-3-methoxy-2-(trifluoromethoxy)-    (CAS #104159-55-9).

In another aspect, the invention provides methods of inducing anesthesiain a subject. In some embodiments, the methods comprise administering tothe subject via the respiratory system an effective amount of a compoundor a mixture of compounds of Formula III:

-   -   wherein:    -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ independently are selected        from H, X, CX₃, CHX₂, CH₂X and C₂X₅; and    -   wherein X is a halogen, the compound has a vapor pressure of at        least 0.1 atmospheres (76 mmHg) at 25° C., and the number of        hydrogen atoms of Formula III do not exceed the number of carbon        atoms, thereby inducing anesthesia in the subject. In various        embodiments, X is a halogen selected from the group consisting        of F, Cl, Br and I. In some embodiments, X is F. In some        embodiments, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ independently are        selected from H, F, Cl, Br, I, CF₃, CHF₂, CH₂F, C₂F₅, CCl₃,        CHCl₂, CH₂Cl, C₂Cl₅, CCl₂F, CClF₂, CHClF, C₂ClF₄, C₂Cl₂F₃,        C₂Cl₃F₂, and C₂Cl₄F. In some embodiments, the compound is        selected from the group consisting of:

-   a) 1,4-Dioxane, 2,2,3,3,5,6-hexafluoro- (CAS #362631-99-0);

-   b) 1,4-Dioxane, 2,3-dichloro-2,3,5,5,6,6-hexafluoro- (CAS    #135871-00-0);

-   c) 1,4-Dioxane, 2,3-dichloro-2,3,5,5,6,6-hexafluoro-, trans- (9CI)    (CAS #56625-45-7);

-   d) 1,4-Dioxane, 2,3-dichloro-2,3,5,5,6,6-hexafluoro-, cis- (9CI)    (CAS #56625-44-6);

-   e) 1,4-Dioxane, 2,2,3,5,6,6-hexafluoro- (CAS #56269-26-2);

-   f) 1,4-Dioxane, 2,2,3,5,5,6-hexafluoro- (CAS #56269-25-1);

-   g) 1,4-Dioxane, 2,2,3,3,5,6-hexafluoro-, trans- (9CI) (CAS    #34206-83-2);

-   h) 1,4-Dioxane, 2,2,3,5,5,6-hexafluoro-, cis- (9CI) (CAS    #34181-52-7);

-   i) p-Dioxane, 2,2,3,5,5,6-hexafluoro-, trans- (8CI) (CAS    #34181-51-6);

-   j) 1,4-Dioxane, 2,2,3,5,6,6-hexafluoro-, cis- (9CI) (CAS    #34181-50-5);

-   k) p-Dioxane, 2,2,3,5,6,6-hexafluoro-, trans- (8CI) (CAS    #34181-49-2);

-   1) 1,4-Dioxane, 2,2,3,3,5,6-hexafluoro-, (5R,6S)-rel- (CAS    #34181-48-1);

-   m) 1,4-Dioxane, 2,2,3,3,5,5,6-heptafluoro- (CAS #34118-18-8); and

-   n) 1,4-Dioxane, 2,2,3,3,5,5,6,6-octafluoro- (CAS #32981-22-9).

In another aspect, the invention provides methods of inducing anesthesiain a subject. In some embodiments, the methods comprise administering tothe subject via the respiratory system an effective amount of a compoundor a mixture of compounds of Formula IV:

-   -   wherein:    -   R¹, R², R³, R⁴, R⁵ and R⁶ independently are selected from H, X,        CX₃, CHX₂, CH₂X and C₂X₅; and    -   wherein X is a halogen, the compound has a vapor pressure of at        least 0.1 atmospheres (76 mmHg) at 25° C., and the number of        hydrogen atoms of Formula IV do not exceed the number of carbon        atoms, thereby inducing anesthesia in the subject. In various        embodiments, X is a halogen selected from the group consisting        of F, Cl, Br and I. In some embodiments, X is F. In some        embodiments, R¹, R², R³, R⁴, R⁵ and R⁶ independently are        selected from H, F, Cl, Br, I, CF₃, CHF₂, CH₂F, C₂F₅, CCl₃,        CHCl₂, CH₂Cl, C₂Cl₅, CCl₂F, CClF₂, CHClF, C₂ClF₄, C₂Cl₂F₃,        C₂Cl₃F₂, and C₂Cl₄F. In some embodiments, the compound is        selected from the group consisting of:

-   a) 1,3-Dioxolane, 2,4,4,5-tetrafluoro-5-(trifluoromethyl)- (CAS    #344303-08-8);

-   b) 1,3-Dioxolane, 2-chloro-4,4,5-trifluoro-5-(trifluoromethyl)- (CAS    #344303-05-5);

-   c) 1,3-Dioxolane, 4,4,5,5-tetrafluoro-2-(trifluoromethyl)- (CAS    #269716-57-6);

-   d) 1,3-Dioxolane, 4-chloro-2,2,4-trifluoro-5-(trifluoromethyl)- (CAS    #238754-29-5);

-   e) 1,3-Dioxolane, 4,5-dichloro-2,2,4,5-tetrafluoro-, trans- (9CI)    (CAS #162970-78-7);

-   f) 1,3-Dioxolane, 4,5-dichloro-2,2,4,5-tetrafluoro-, cis- (9CI) (CAS    #162970-76-5);

-   g) 1,3-Dioxolane, 4-chloro-2,2,4,5,5-pentafluoro- (CAS    #139139-68-7);

-   h) 1,3-Dioxolane, 4,5-dichloro-2,2,4,5-tetrafluoro- (CAS    #87075-00-1);

-   i) 1,3-Dioxolane, 2,4,4,5-tetrafluoro-5-(trifluoromethyl)-, trans-    (9CI) (CAS #85036-66-4);    j) 1,3-Dioxolane, 2,4,4,5-tetrafluoro-5-(trifluoromethyl)-, cis-    (9CI) (CAS #85036-65-3);    k) 1,3-Dioxolane, 2-chloro-4,4,5-trifluoro-5-(trifluoromethyl)-,    trans- (9CI) (CAS #85036-60-8);    l) 1,3-Dioxolane, 2-chloro-4,4,5-trifluoro-5-(trifluoromethyl)-,    cis- (9CI) (CAS #85036-57-3);    m) 1,3-Dioxolane, 2,2-dichloro-4,4,5,5-tetrafluoro- (CAS    #85036-55-1);    n) 1,3-Dioxolane, 4,4,5-trifluoro-5-(trifluoromethyl)- (CAS    #76492-99-4);    o) 1,3-Dioxolane, 4,4-difluoro-2,2-bis(trifluoromethyl)- (CAS    #64499-86-1);    p) 1,3-Dioxolane, 4,5-difluoro-2,2-bis(trifluoromethyl)-, cis- (9CI)    (CAS #64499-85-0);    q) 1,3-Dioxolane, 4,5-difluoro-2,2-bis(trifluoromethyl)-, trans-    (9CI) (CAS #64499-66-7);    r) 1,3-Dioxolane, 4,4,5-trifluoro-2,2-bis(trifluoromethyl)- (CAS    #64499-65-6);    s) 1,3-Dioxolane, 2,4,4,5,5-pentafluoro-2-(trifluoromethyl)- (CAS    #55135-01-8);    t) 1,3-Dioxolane, 2,2,4,4,5,5-hexafluoro- (CAS #21297-65-4); and    u) 1,3-Dioxolane, 2,2,4,4,5-pentafluoro-5-(trifluoromethyl)- (CAS    #19701-22-5).

In another aspect, the invention provides methods of inducing anesthesiain a subject. In some embodiments, the methods comprise administering tothe subject via the respiratory system an effective amount of a compoundor a mixture of compounds of Formula V:

-   -   wherein:    -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ independently are        selected from H, X, CX₃, CHX₂, CH₂X and C₂X₅; and    -   wherein X is a halogen, the compound has a vapor pressure of at        least 0.1 atmospheres (76 mmHg) at 25° C., and the number of        hydrogen atoms of Formula V do not exceed the number of carbon        atoms, thereby inducing anesthesia in the subject. In various        embodiments, X is a halogen selected from the group consisting        of F, Cl, Br and I. In some embodiments, X is F. In some        embodiments, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰        independently are selected from H, F, Cl, Br, I, CF₃, CHF₂,        CH₂F, C₂F₅, CCl₃, CHCl₂, CH₂Cl, C₂Cl₅, CCl₂F, CClF₂, CHClF,        C₂ClF₄, C₂Cl₂F₃, C₂Cl₃F₂, and C₂Cl₄F. In some embodiments, the        compound is selected from the group consisting of:

-   a) Cyclopentane, 5-chloro-1,1,2,2,3,3,4,4-octafluoro- (CAS    #362014-70-8);

-   b) Cyclopentane, 1,1,2,2,3,4,4,5-octafluoro- (CAS #773-17-1);

-   c) Cyclopentane, 1,1,2,2,3,3,4,5-octafluoro- (CAS #828-35-3);

-   d) Cyclopentane, 1,1,2,3,3,4,5-heptafluoro- (CAS #3002-03-7);

-   e) Cyclopentane, 1,1,2,2,3,3,4,4-octafluoro- (CAS #149600-73-7);

-   f) Cyclopentane, 1,1,2,2,3,4,5-heptafluoro- (CAS #1765-23-7);

-   g) Cyclopentane, 1,1,2,3,4,5-hexafluoro- (CAS #699-38-7);

-   h) Cyclopentane, 1,1,2,2,3,3,4-heptafluoro- (CAS #15290-77-4);

-   i) Cyclopentane, 1,1,2,2,3,4-hexafluoro- (CAS #199989-36-1);

-   j) Cyclopentane, 1,1,2,2,3,3-hexafluoro- (CAS #123768-18-3); and

-   k) Cyclopentane, 1,1,2,2,3-pentafluoro- (CAS #1259529-57-1). In some    embodiments, the compound is selected from the group consisting of:

-   c) Cyclopentane, 1,1,2,2,3,3,4,5-octafluoro- (CAS #828-35-3);

-   e) Cyclopentane, 1,1,2,2,3,3,4,4-octafluoro- (CAS #149600-73-7); and

-   h) Cyclopentane, 1,1,2,2,3,3,4-heptafluoro- (CAS #15290-77-4).

In another aspect, the invention provides methods of inducing anesthesiain a subject. In some embodiments, the methods comprise administering tothe subject via the respiratory system an effective amount of1,1,2,2,3,3,4,4-octafluoro-cyclohexane (CAS #830-15-9), thereby inducinganesthesia in the subject.

In another aspect, the invention provides methods of inducing anesthesiain a subject. In some embodiments, the methods comprise administering tothe subject via the respiratory system an effective amount of a compoundor a mixture of compounds of Formula VI:

-   -   wherein:    -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ independently are selected        from H, X, CX₃, CHX₂, CH₂X and C₂X₅; and    -   wherein X is a halogen, the compound has a vapor pressure of at        least 0.1 atmospheres (76 mmHg) at 25° C., and the number of        hydrogen atoms of Formula VI do not exceed the number of carbon        atoms, thereby inducing anesthesia in the subject. In various        embodiments, X is a halogen selected from the group consisting        of F, Cl, Br and I. In some embodiments, X is F. In some        embodiments, R′, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ independently are        selected from H, F, Cl, Br, I, CF₃, CHF₂, CH₂F, C₂F₅, CCl₃,        CHCl₂, CH₂Cl, C₂Cl₅, CCl₂F, CClF₂, CHClF, C₂ClF₄, C₂Cl₂F₃,        C₂Cl₃F₂, and C₂Cl₄F. In some embodiments, the compound is        selected from the group consisting of:

-   a) Furan, 2,3,4,4-tetrafluorotetrahydro-2,3-bis(trifluoromethyl)-    (CAS #634191-25-6);

-   b) Furan, 2,2,3,3,4,4,5-heptafluorotetrahydro-5-(trifluoromethyl)-    (CAS #377-83-3);

-   c) Furan, 2,2,3,3,4,5,5-heptafluorotetrahydro-4-(trifluoromethyl)-    (CAS #374-53-8);

-   d) Furan, 2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,    (2a,3β,4a)- (9CI) (CAS #133618-53-8);

-   e) Furan, 2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,    (2a,3a,4β)- (CAS #133618-52-7);

-   f) Furan, 2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,    (2a,3β,4a)- (9CI) (CAS #133618-53-8);

-   g) Furan, 2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,    (2a,3a,4(3)- (9CI) (CAS #133618-52-7);

-   h) Furan, 2,2,3,3,5,5-hexafluorotetrahydro-4-(trifluoromethyl)- (CAS    #61340-70-3);

-   i) Furan, 2,3-difluorotetrahydro-2,3-bis(trifluoromethyl)- (CAS    #634191-26-7);

-   j) Furan, 2-chloro-2,3,3,4,4,5,5-heptafluorotetrahydro- (CAS    #1026470-51-8);

-   k) Furan, 2,2,3,3,4,4,5-heptafluorotetrahydro-5-methyl- (CAS    #179017-83-5);

-   l) Furan, 2,2,3,3,4,5-hexafluorotetrahydro-5-(trifluoromethyl)-,    trans- (9CI) (CAS #133618-59-4); and

-   m) Furan, 2,2,3,3,4,5-hexafluorotetrahydro-5-(trifluoromethyl)-,    cis- (9CI) (CAS #133618-49-2).

In another aspect, the invention provides methods of inducing anesthesiain a subject. In some embodiments, the methods comprise administering tothe subject via the respiratory system an effective amount of a compoundor mixture of compounds of Formula VII:

-   -   wherein:    -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ independently are        selected from H, X, CX₃, CHX₂, CH₂X, and C₂X₅; and    -   wherein X is a halogen, the compound has a vapor pressure of at        least 0.1 atmospheres (76 mmHg) at 25° C., and the number of        hydrogen atoms of Formula VII do not exceed the number of carbon        atoms, thereby inducing anesthesia in the subject. In various        embodiments, X is a halogen selected from the group consisting        of F, Cl, Br and I. In some embodiments, X is F. In some        embodiments, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰        independently are selected from H, F, Cl, Br, I, CF₃, CHF₂,        CH₂F, C₂F₅, CCl₃, CHCl₂, CH₂Cl, C₂Cl₅, CCl₂F, CClF₂, CHClF,        C₂ClF₄, C₂Cl₂F₃, C₂Cl₃F₂, and C₂Cl₄F. In some embodiments, the        compound is selected from the group consisting of:

-   a) 2H-Pyran, 2,2,3,3,4,5,5,6,6-nonafluorotetrahydro-4- (CAS    #71546-79-7);

-   b) 2H-Pyran,    2,2,3,3,4,4,5,5,6-nonafluorotetrahydro-6-(trifluoromethyl)- (CAS    #356-47-8);

-   c) 2H-Pyran,    2,2,3,3,4,4,5,6,6-nonafluorotetrahydro-5-(trifluoromethyl)- (CAS    #61340-74-7);

-   d) 2H-Pyran, 2,2,6,6-tetrafluorotetrahydro-4-(trifluoromethyl)- (CAS    #657-48-7);

-   e) 2H-Pyran, 2,2,3,3,4,4,5,5,6-nonafluorotetrahydro-6-methyl- (CAS    #874634-55-6);

-   f) Perfluorotetrahydropyran (CAS #355-79-3);

-   g) 2H-Pyran, 2,2,3,3,4,5,5,6-octafluorotetrahydro-, (4R,6S)-rel-    (CAS #362631-93-4); and

-   h) 2H-Pyran, 2,2,3,3,4,4,5,5,6-nonafluorotetrahydro- (CAS    #65601-69-6).

In various embodiments, the compound has a molar water solubility ofless than about 1.1 mM and greater than about 0.016 mM. In variousembodiments, the compound potentiates GABA_(A) receptors, but does notinhibit NMDA receptors.

In some embodiments, the subject is a mammal. In some embodiments, thesubject is a human.

In a further aspect, the invention provides compositions comprising acompound or a mixture of compounds used in the above and hereindescribed methods, wherein the composition is formulated forinhalational or pulmonary delivery of the compound or mixture ofcompounds.

In a further aspect, the invention provides methods of selecting ananesthetic that preferentially activates or potentiates GABA_(A)receptors without inhibiting NMDA receptors. In some embodiments, themethods comprise:

a) determining the molar water solubility of the anesthetic; and

b) selecting an anesthetic with a molar water solubility below about 1.1mM, wherein the anesthetic selectively potentiates GABA_(A) receptorsand does not inhibit NMDA receptors, whereby an anesthetic thatpreferentially activates or potentiates GABA_(A) receptors withoutinhibiting NMDA receptors is selected. In various embodiments, theanesthetic is an inhalational anesthetic. In some embodiments, theanesthetic is selected from the group consisting of halogenatedalcohols, halogenated diethers, halogenated dioxanes, halogenateddioxolanes, halogenated cyclopentanes, halogenated cyclohexanes,halogenated tetrahydrofurans and halogenated tetrahydropyrans, whereinthe anesthetic has a vapor pressure of at least 0.1 atmospheres (76mmHg) at 25° C., and the number of hydrogen atoms do not exceed thenumber of carbon atoms. In some embodiments, the anesthetic is selectedfrom the compounds administered in the methods described above andherein. In some embodiments, the anesthetic is selected from the groupconsisting of nonane, midazolam, diazepam, undecanol, etomidate, 1,2dichlorohexafluorocyclobutane, and analogs thereof.

In a related aspect, the invention provides methods of selecting ananesthetic that both potentiates GABA_(A) receptors and inhibits NMDAreceptors. In some embodiments, the methods comprise:

a) determining the molar water solubility of the anesthetic; and

b) selecting an anesthetic with a molar water solubility above about 1.1mM, wherein the anesthetic both potentiates GABA_(A) receptors andinhibits NMDA receptors, whereby an anesthetic that both potentiatesGABA_(A) receptors and inhibits NMDA receptors is selected. In variousembodiments, the anesthetic is an inhalational anesthetic. In someembodiments, the anesthetic is selected from the group consisting ofhalogenated alcohols, halogenated diethers, halogenated dioxanes,halogenated dioxolanes, halogenated cyclopentanes, halogenatedcyclohexanes, halogenated tetrahydrofurans and halogenatedtetrahydropyrans, wherein the anesthetic has a vapor pressure of atleast 0.1 atmospheres (76 mmHg) at 25° C., and the number of hydrogenatoms do not exceed the number of carbon atoms. In some embodiments, theanesthetic is selected from the compounds administered in the methodsdescribed above and herein. In some embodiments, the anesthetic isselected from the group consisting of sevoflurane, propofol, ketamine,isoflurane, enflurane, dizocilpine, desflurane, halothane, cyclopropane,chloroform, 2,6-dimethylphenol, methoxyflurane, diethyl ether, nitrousoxide, ethanol, and analogs thereof.

In another aspect, the invention of determining the specificity of ananesthetic for an anesthetic-sensitive receptor comprising determiningwhether the molar water solubility of the anesthetic is above or below apredetermined solubility threshold concentration for ananesthetic-sensitive receptor,

wherein an anesthetic with a molar water solubility below about 1.2 mMdoes not inhibit Na_(v) channels, but can inhibit NMDA receptors,potentiate two-pore domain potassium channels (K_(2P)), potentiateglycine receptors and potentiate GABA_(A) receptors;

wherein an anesthetic with a molar water solubility below about 1.1 mMdoes not inhibit Na_(v) channels or inhibit NMDA receptors, but canpotentiate two-pore domain potassium channels (K_(2P)), potentiateglycine receptors and potentiate GABA_(A) receptors;

wherein an anesthetic with a molar water solubility below about 0.26 mMdoes not inhibit Na_(v) channels, inhibit NMDA receptors or potentiatetwo-pore domain potassium channel (K_(2P)) currents, but can potentiateglycine receptors and potentiate GABA_(A) receptors; and

wherein an anesthetic with a molar water solubility below about 68 μMdoes not inhibit Na_(v) channels, inhibit NMDA receptors, potentiatetwo-pore domain potassium channel (K_(2P)) currents, or potentiateGABA_(A) receptors but can potentiate glycine receptors; therebydetermining the specificity of an anesthetic for an anesthetic-sensitivereceptor. In various embodiments, the anesthetic is an inhalationalanesthetic. In some embodiments, the anesthetic is selected from thegroup consisting of halogenated alcohols, halogenated diethers,halogenated dioxanes, halogenated dioxolanes, halogenated cyclopentanes,halogenated cyclohexanes, halogenated tetrahydrofurans and halogenatedtetrahydropyrans, wherein the anesthetic has a vapor pressure of atleast 0.1 atmospheres (76 mmHg) at 25° C., and the number of hydrogenatoms do not exceed the number of carbon atoms. In some embodiments, theanesthetic is selected from the compounds administered in the methodsdescribed above and herein.

In another aspect, the invention provides methods of modulating thespecificity of an anesthetic for an anesthetic-sensitive receptor. Insome embodiments, the methods comprise adjusting the molar watersolubility of the anesthetic to be above a predetermined watersolubility threshold concentration for an anesthetic-sensitive receptorthat the anesthetic can modulate or adjusting the molar water solubilityof the anesthetic to be below a predetermined molar water solubilitythreshold concentration for an anesthetic-sensitive receptor that theanesthetic cannot modulate;

wherein an anesthetic with a molar water solubility below about 1.2 mMdoes not inhibit Na_(v) channels, but can inhibit NMDA receptors,potentiate two-pore domain potassium channels (K_(2P)), potentiateglycine receptors and potentiate GABA_(A) receptors; wherein ananesthetic with a molar water solubility below about 1.1 mM does notinhibit Na_(v) channels or inhibit NMDA receptors, but can potentiatetwo-pore domain potassium channels (K_(2P)), potentiate glycinereceptors and potentiate GABA_(A) receptors;

wherein an anesthetic with a molar water solubility below about 0.26 mMdoes not inhibit Na_(v) channels, inhibit NMDA receptors or potentiatetwo-pore domain potassium channel (K_(2P)) currents, but can potentiateglycine receptors and potentiate GABA_(A) receptors; and

wherein an anesthetic with a molar water solubility below about 68 μMdoes not inhibit Na_(v) channels, inhibit NMDA receptors, potentiatetwo-pore domain potassium channel (K_(2P)) currents, or potentiateGABA_(A) receptors but can potentiate glycine receptors; therebydetermining the specificity of an anesthetic for an anesthetic-sensitivereceptor. In various embodiments, the anesthetic is an inhalationalanesthetic or an analog thereof. In some embodiments, the anesthetic isselected from the group consisting of halogenated alcohols, halogenateddiethers, halogenated dioxanes, halogenated dioxolanes, halogenatedcyclopentanes, halogenated cyclohexanes, halogenated tetrahydrofuransand halogenated tetrahydropyrans, wherein the anesthetic has a vaporpressure of at least 0.1 atmospheres (76 mmHg) at 25° C., and the numberof hydrogen atoms do not exceed the number of carbon atoms. In someembodiments, the anesthetic is selected from the compounds administeredin the methods described above and herein. In some embodiments, theanesthetic is selected from the group consisting of nonane, midazolam,diazepam, undecanol, etomidate, 1,2-dichlorohexafluorocyclobutane, andanalogs thereof. In some embodiments, the anesthetic is selected fromthe group consisting of sevoflurane, propofol, ketamine, isoflurane,enflurane, dizocilpine, desflurane, halothane, cyclopropane, chloroform,2,6-dimethylphenol, methoxyflurane, diethyl ether, nitrous oxide,ethanol, and analogs thereof. In some embodiments, the anesthetic isadjusted to have a molar water solubility of less than about 1.1 mM andpotentiates GABA_(A) receptors but does not inhibit NMDA receptors. Insome embodiments, the anesthetic is adjusted to have a molar watersolubility of greater than about 1.1 mM and both potentiates GABA_(A)receptors and inhibits NMDA receptors.

Definitions

The term “inhalational anesthetic” refers to gases or vapors thatpossess anesthetic qualities that are administered by breathing throughan anesthesia mask or ET tube connected to an anesthetic machine.Exemplary inhalational anesthetics include without limitation volatileanesthetics (halothane, isoflurane, sevoflurane and desflurane) and thegases (ethylene, nitrous oxide and xenon).

The term “injectable anesthetic or sedative drug” refers to anestheticsor sedatives that can be injected under the skin via a hypodermic needleand syringe and that through actions on nerves in the brain or spinalcord can either render an individual insensible to painful stimuli, ordecrease an individual's perceived sensation of painful stimuli, orinduce within an individual an amnestic and/or calming effect.

The term “anesthetic-sensitive receptor” refers to a cell membraneprotein that binds to an anesthetic agent and whose function ismodulated by the binding of that anesthetic agent. Anesthetic-sensitivereceptors are usually ion channels or cell membrane that are indirectlylinked to ion channels via second messenger systems (such as G-proteinsand tyrosine kinases) and can have 2, 3, 4, or 7 transmembrane regions.Such receptors can be comprised of 2 or more subunits and function aspart of a protein complex. Activation or inhibition of these receptorsresults in either a direct change in ion permeability across the cellmembrane that alters the cell resting membrane potential, or alters theresponse of the cell receptor to its endogenous ligand in such a waythat the change in ion permeability and cell membrane potential normallyelicited by the endogenous ligand is changed. Exemplaryanesthetic-sensitive receptors include gamma-aminobutyric acid (GABA)receptors, N-methyl-D-aspartate (NMDA) receptors, voltage-gated sodiumion channels, voltage-gated potassium ion channels, two-pore domainpotassium channels, adrenergic receptors, acetylcholine receptors,glycine and opioid receptors.

The term “effective amount” or “pharmaceutically effective amount” referto the amount and/or dosage, and/or dosage regime of one or morecompounds necessary to bring about the desired result e.g., an amountsufficient to effect anesthesia, render the subject unconscious and/orimmobilize the subject.

As used herein, the term “pharmaceutically acceptable” refers to amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of the compound useful within theinvention, and is relatively non-toxic, i.e., the material may beadministered to an individual without causing undesirable biologicaleffects or interacting in a deleterious manner with any of thecomponents of the composition in which it is contained.

As used herein, the language “pharmaceutically acceptable salt” refersto a salt of the administered compound prepared from pharmaceuticallyacceptable non-toxic acids and bases, including inorganic acids,inorganic bases, organic acids, inorganic bases, solvates, hydrates, andclathrates thereof.

As used herein, the term “composition” or “pharmaceutical composition”refers to a mixture of at least one compound useful within the inventionwith a pharmaceutically acceptable carrier. The pharmaceuticalcomposition facilitates administration of the compound to a subject.

The phrase “cause to be administered” refers to the actions taken by amedical professional (e.g., a physician), or a person controllingmedical care of a subject, that control and/or permit the administrationof the agent(s)/compound(s) at issue to the subject. Causing to beadministered can involve diagnosis and/or determination of anappropriate therapeutic or prophylactic regimen, and/or prescribingparticular agent(s)/compounds for a subject. Such prescribing caninclude, for example, drafting a prescription form, annotating a medicalrecord, and the like.

The terms “patient,” “individual,” “subject” interchangeably refer toany mammal, e.g., a human or non-human mammal, e.g., a non-humanprimate, a domesticated mammal (e.g., canine, feline), an agriculturalmammal (e.g., equine, bovine, ovine, porcine), or a laboratory mammal(e.g., rattus, murine, lagomorpha, hamster).

The term “molar water solubility” refers to the calculated or measurednumber of moles per liter of a compound present at a saturatedconcentration in pure water at 25° C. and at pH=7.0.

The term “solubility cut-off value” refers to the threshold watersolubility concentration of an anesthetic compound that can activate aparticular anesthetic-sensitive receptor. If the water solubility of theanesthetic agent is below the solubility cut-off value for a particularanesthetic-sensitive receptor, then the agent will not activate thatreceptor. If the water solubility of the anesthetic agent is above thesolubility cut-off value for a particular anesthetic-sensitive receptor,then the agent can, but need not, activate that receptor.

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbonradical, having the number of carbon atoms designated (i.e. C₁₋₈ meansone to eight carbons). Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. For each of the definitionsherein (e.g., alkyl, alkoxy, alkylamino, alkylthio, alkylene,haloalkyl), when a prefix is not included to indicate the number of mainchain carbon atoms in an alkyl portion, the radical or portion thereofwill have 24 or fewer, for example, 20, 18, 16, 14, 12, 10, 8, 6 orfewer, main chain carbon atoms.

The term “alkylene” by itself or as part of another substituent means anunsaturated hydrocarbon chain containing 1 or more carbon-carbon doublebonds. Typically, an alkyl (or alkylene) group will have from 1 to 24carbon atoms, with those groups having 10 or fewer carbon atoms beingpreferred in the present invention. A “lower alkyl” or “lower alkylene”is a shorter chain alkyl or alkylene group, generally having four orfewer carbon atoms.

The term “cycloalkyl” refers to hydrocarbon rings having the indicatednumber of ring atoms (e.g., C₃₋₆cycloalkyl) and being fully saturated orhaving no more than one double bond between ring vertices. One or two Catoms may optionally be replaced by a carbonyl. “Cycloalkyl” is alsomeant to refer to bicyclic and polycyclic hydrocarbon rings such as, forexample, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. When a prefixis not included to indicate the number of ring carbon atoms in acycloalkyl, the radical or portion thereof will have 8 or fewer ringcarbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. Additionally, for dialkylaminogroups, the alkyl portions can be the same or different and can also becombined to form a 3 to 8 membered ring with the nitrogen atom to whicheach is attached. Accordingly, a group represented as —NR^(aRb) is meantto include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and thelike.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“C₁₋₄ haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “aryl” means a monovalent monocyclic, bicyclic or polycyclicaromatic hydrocarbon radical of 5 to 14 ring atoms which isunsubstituted or substituted independently with one to foursubstituents, preferably one, two, or three substituents selected fromalkyl, cycloalkyl, cycloalkyl-alkyl, halo, cyano, hydroxy, alkoxy,amino, acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy,heteroalkyl, COR (where R is hydrogen, alkyl, cycloalkyl,cycloalkyl-alkyl cut, phenyl or phenylalkyl, aryl or arylalkyl),—(CR′R″)_(n)—COOR (where n is an integer from 0 to 5, R′ and R″ areindependently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl,cycloalkylalkyl cut, phenyl or phenylalkyl aryl or arylalkyl) or—(CR′R″)_(n)—CONR^(aRb) (where n is an integer from 0 to 5, R′ and R″are independently hydrogen or alkyl, and R^(a) and R^(b) are,independently of each other, hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, phenyl or phenylalkyl, aryl or arylalkyl). Morespecifically the term aryl includes, but is not limited to, phenyl,biphenyl, 1-naphthyl, and 2-naphthyl, and the substituted forms thereof.Similarly, the term “heteroaryl” refers to those aryl groups wherein oneto five heteroatoms or heteroatom functional groups have replaced a ringcarbon, while retaining aromatic properties, e.g., pyridyl, quinolinyl,quinazolinyl, thienyl, and the like. The heteroatoms are selected fromN, O, and S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. Aheteroaryl group can be attached to the remainder of the moleculethrough a heteroatom. Non-limiting examples of aryl groups includephenyl, naphthyl and biphenyl, while non-limiting examples of heteroarylgroups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl,quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalaziniyl,benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl,benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl,thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl,imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl,quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl,pyrrolyl, thiazolyl, furyl, thienyl and the like. For brevity, the termaryl, when used in combination with other radicals (e.g., aryloxy,arylalkyl) is meant to include both aryl groups and heteroaryl groups asdescribed above.

Substituents for the aryl groups are varied and are generally selectedfrom: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′,—CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′,—NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —N₃, perfluoro(C₁₋₄)alkoxy, andperfluoro(C₁₋₄)alkyl, in a number ranging from zero to the total numberof open valences on the aromatic ring system; and where R′, R″ and R′″are independently selected from hydrogen, C₁₋₈ alkyl, C₃₋₆ cycloalkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl unsubstituted aryl and heteroaryl,(unsubstituted aryl)-C₁₋₄ alkyl, and unsubstituted aryloxy-C₁₋₄ alkyl.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—, —CH₂—or a single bond, and q is an integer of from 0 to 2. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula-A-(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —NH—, —S(O)—,—S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integer of from 1 to3. One of the single bonds of the new ring so formed may optionally bereplaced with a double bond. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula —(CH₂)_(s)—X—(CH₂)_(t)—, where s and tare independently integers of from 0 to 3, and X is —O—, —S(O)—,—S(O)₂—, or —S(O)₂NR′—. The substituent R′ in and —S(O)₂NR′— is selectedfrom hydrogen or unsubstituted C₁₋₆ alkyl.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a diagram showing the effect of drug dose on thepercent contribution to MAC of 2 anesthetic-sensitive receptors (R1 andR2). The drug shows high-affinity for R1, but is unable to produce ananesthetic effect by itself. A small contribution from low-affinityinteractions with R2 is necessary to produce a 100% anesthetic effect(MAC).

FIG. 2 illustrates a summary of ion channel modulation as a function ofcalculated anesthetic molar solubility in unbuffered water at 25° C.(values from SciFinder Scholar). Drugs that modulate 4-transmembranereceptors (TM4) or neither receptor type are shown as open circles (∘,A-F) below the dotted horizontal solubility line. Drugs that modulateboth 3-transmembrane (TM3) and TM4 receptors are shown as small blackcircles (●, G-U) above the dotted horizontal solubility line. A=nonane,B=midazolam (Nistri, et al., Neurosci Lett (1983) 39:199-204),C=diazepam (Macdonald, et al., Nature (1978) 271:563-564), D=undecanol(Dildy-Mayfield, et al., Br J Pharmacol (1996) 118:378-384), E=etomidate(Flood, et al., Anesthesiology (2000) 92:1418-1425),F=1,2-dichlorohexafluorocyclobutane (Kendig, et al., Eur J Pharmacol(1994) 264:427-436), G=sevoflurane (Jenkins, et al., Anesthesiology1999; 90:484-491; Krasowski, Br J Pharmacol (2000) 129:731-743;Hollmann, Anesth Analg (2001) 92:1182-1191, Nishikawa, et al.,Anesthesiology (2003) 99:678-684), H=propofol (Yamakura, et al.,Neurosci Lett (1995) 188:187-190; Hales, et al., Br J Pharmacol (1991)104:619-628), I=ketamine (Flood, et al., Anesthesiology (2000)92:1418-1425; Hollmann, Anesth Analg (2001) 92:1182-1191; Yamakura, etal., Anesthesiology (2000) 92:1144-1153), J=isoflurane (Jenkins, et al.,Anesthesiology (1999) 90:484-491; Krasowski, et al., Br J Pharmacol(2000) 129:731-743; Hollmann, et al., Anesth Analg (2001) 92:1182-1191;Yamakura, et al., Anesthesiology (2000) 93:1095-1101; Ogata, et al., JPharmacol Exp Ther (2006) 318:434-443), K=enflurane (Krasowski, et al.,Br J Pharmacol (2000) 129:731-743; Martin, et al. Biochem Pharmacol(1995) 49:809-817), L=dizocilpine (Yamakura, et al., Anesthesiology(2000) 92:1144-1153; Wong, et al., Proc Natl Acad Sci USA (1986)83:7104-7108), M=desflurane (Hollmann, et al., Anesth Analg (2001)92:1182-1191; Nishikawa, et al., Anesthesiology (2003) 99:678-684),N=halothane (Jenkins, et al., Anesthesiology (1999) 90:484-491; Ogata,et al., J Pharmacol Exp Ther (2006) 318:434-443; Martin, et al., BiochemPharmacol (1995) 49:809-817), O=cyclopropane (Ogata, et al., J PharmacolExp Ther (2006) 318:434-443; Hara, et al., Anesthesiology (2002)97:1512-1520.), P=chloroform,61 Q=2,6-dimethylphenol,65 R=methoxyflurane(Jenkins, et al., Anesthesiology (1999) 90:484-491; Krasowski, et al.,Br J Pharmacol (2000) 129:731-743; Martin, et al. Biochem Pharmacol(1995) 49:809-817), S=diethyl ether (Krasowski, et al., Br J Pharmacol(2000) 129:731-743; Martin, et al. Biochem Pharmacol (1995) 49:809-817),T=nitrous oxide (Yamakura, et al., Anesthesiology (2000) 93:1095-1101;Ogata, et al., J Pharmacol Exp Ther (2006) 318:434-443), U=ethanol(Yamakura, et al., Anesthesiology (2000) 93:1095-1101). Mostconventional and experimental agents modulate members of 4-transmembraneion channels (e.g., y-aminobutyric acid Type A or GABA_(A) receptors,glycine receptors, and nicotinic acetylcholine receptors) and3-transmembrane ion channels (e.g., N-methyl-d-aspartate or NMDAreceptors). However, agents with low molar water solubility fail tomodulate 3-transmembrane receptors.

FIG. 3 illustrates sample two-electrode voltage clamp recordings fromoocytes expressing either GABA_(A) receptors (left) or NMDA receptors(right). Black bars (

) represent periods of agonist exposure, and arrows (↔) representperiods of saturated alkane exposure. Both butane and pentane positivelymodulate GABA_(A) receptors. Butane negatively modulates NMDA receptors,but pentane produces no effect. Hence, NMDA receptors exhibit an alkanecut-off between butane and pentane.

FIG. 4 illustrates a summary of receptor cut-off effects as a functionof molar water solubility. For each hydrocarbon functional group, whitebars represent compounds that modulate both GABA_(A) and NMDA receptors,and black bars represent compounds that modulate GABA_(A) receptors buthave no effect on NMDA receptors at a saturating concentration.Intervening grey bars represent solubility values for which no dataexist.

FIG. 5 illustrates a summary of receptor cut-off effects as a functionof the number of drug carbon atoms. Refer to FIG. 3 for key information.No receptor cut-off pattern is evident as a function of the number ofdrug carbon atoms.

FIG. 6 illustrates a summary of receptor cut-off effects as a functionof the calculated molecular volume of each drug. Refer to FIG. 3 for keyinformation. No receptor cut-off pattern is evident as a function ofmolecular volume.

FIG. 7 illustrates a graph of ion channel and receptor modulation as afunction of molar water solubility. Drugs modulate channel or receptoractivity over the solubility range indicated by the white bar and do notmodulate activity over the solubility range indicated by the black bar.The grey region represents the 95% confidence interval around thesolubility cut-off for 3 different hydrocarbon types (1-alcohols,n-alkanes, and dialkyl ethers) for all channels and receptors except theNMDA receptor, on which a total of 13 different hydrocarbon types werestudied.

DETAILED DESCRIPTION

I. Introduction

The present invention is based, in part, on the surprising discoverythat the specificity of an anesthetic for an anesthetic-sensitivereceptor can be modulated (e.g., increased or decreased) by altering thewater solubility of the anesthetic. Based on the threshold solubilitycut-off values for different families of anesthetic-sensitive receptors,anesthetics can be designed to activate subsets of receptors with awater solubility cut-off value that is less than the water solubility ofthe anesthetic, while not activating receptors with a water solubilitycut-off value that is greater than the water solubility of theanesthetic. Generally, anesthetics with a relatively higher watersolubility activate a larger number of anesthetic-sensitive receptors;anesthetics with a relatively lower water solubility activate feweranesthetic-sensitive receptors. The present discovery finds use indetermining the specificity of a particular anesthetic for differentanesthetic-sensitive receptors, e.g., by comparing the water solubilityof the anesthetic with the threshold solubility cut-off values ofdifferent anesthetic-sensitive receptors. The present discovery alsofinds use in guiding the rational chemical modification orderivitization of an anesthetic to adjust its water solubility andspecificity for different anesthetic-sensitive receptors.

Some anesthetics bind with high affinity (low EC50) to either4-transmembrane receptors (i.e., GABA_(A)) or 3-transmembrane receptors(i.e., NMDA), but not to members of both receptor superfamilies.However, drugs with sufficient amphipathic properties can modulatemembers of both receptor superfamilies; this is true not only forketamine and propofol, but for many conventional and experimentalanesthetics (FIG. 2). Based the information in FIG. 2, sufficient watersolubility appears sufficient to allow modulation of phylogeneticallyunrelated receptor superfamilies. Further, FIG. 2 would suggest thatcompounds with a molar solubility less than approximately 1 mM exhibitreceptor superfamily specificity, but compounds with greater molaraqueous solubility can modulate 3- and 4-transmembrane receptors, ifapplied in sufficient concentrations. The importance of aqueousanesthetic concentration to mediate low-affinity ion channel effectsexplains why receptor point mutations near water cavities in proteins ornear the plasma membrane-extracellular interface can dramatically affectsensitivity to volatile anesthetics (Lobo, et al., Neuropharmacology(2006) 50: 174-81). In addition, the anesthetic cut-off effect withincreasing hydrocarbon chain length may be due to an insufficient molarwater solubility of large hydrophobic molecules (Katz, et al., J TheorBiol (2003) 225: 341-9). In effect, this may not be a size cut-off, buta solubility cut-off.

Anesthetics do not distribute equally throughout the lipid bilayer.Halothane shows a preference for the phospholipid headgroup interface(Vemparala, et al., Biophys J (2006) 91: 2815-25). Xenon atoms preferregions at the lipid-water interface and the central region of thebilayer (Stimson, et al., Cell Mol Biol Lett (2005) 10: 563-9). Theanesthetics cyclopropane, nitrous oxide, desflurane, isoflurane, and1,1,2-trifluoroethane (TFE) all preferentially concentrate at theinterface between water and hexane (Pohorille et al., Toxicol Lett(1998) 100-101: 421-30). However, perfluoroethane, a compoundstructurally similar to TFE, does not exhibit an hydrophilic-hydrophobicinterfacial maxima, and it is both poorly soluble in water and anonimmobilizer (Pohorille, supra). It has been hypothesized thataccumulation of amphipathic anesthetics at the lipid-water interface maydecrease surface tension (Wustneck, et al., Langmuir (2007) 23: 1815-23)and reduce the lateral pressure profile of the membrane phospholipids(Terama, et al., J Phys Chem B (2008) 112: 4131-9). This could alter thehydration status of membrane proteins (Ho, et al., Biophys J (1992) 63:897-902), and thus alter conduction through ion channels. It is possiblethat the “anesthetic sensitivity” of certain channels may simply be amarker of receptors that are subject to modulation by interfacialhydrophilic interactions.

However, there is no reason to presume that the same number ofhydrophilic or hydrophobic anesthetic interactions should be identicalfor dissimilar ion channels. The 2-transmembrane (e.g., P2X, P2Zreceptors), 3-transmembrane (e.g., AMPA, kainite, and NMDA receptors),4-transmembrane (nACh, 5-HT₃, GABA_(A), GABA_(C), and glycinereceptors), and 7-transmembrane (G-protein coupled receptors)superfamilies are phylogenetically unrelated (Foreman J C, Johansen T:Textbook of Receptor Pharmacology, 2nd Edition. Boca Raton, CRC Press,2003). Hence, it seems likely that the number of anesthetic molecules atthe lipid water interface necessary to modulate a receptor should bedifferent for members of different superfamilies, but more similar forchannels within the same superfamily since these share greater sequencehomology.

If non-specific interactions of anesthetics at the lipid-water interfaceare important for low-affinity and promiscuous ion channel modulations,then at least two predictions can be made.

First, sufficient water solubility should be important for interfacialinteractions, and thus any amphipathic molecule with sufficient watersolubility should be able to modulate anesthetic-sensitive channels.This statement is supported by numerous studies that show GABA_(A),glycine, NMDA, two-pore domain potassium channels, and otheranesthetic-sensitive channels can be modulated by conventional andnonconventional anesthetics, including carbon dioxide, ammonia, ketonebodies, and detergents (Yang, et al, Anesth Analg (2008) 107: 868-74;Yang, et al., Anesth Analg (2008) 106: 838-45; Eger, et al., AnesthAnalg (2006) 102: 1397-406; Solt, et al., Anesth Analg (2006) 102:1407-11; Krasowski, et al., J Pharmacol Exp Ther (2001) 297: 338-51;Brosnan, et al., Anesth Analg (2007) 104: 1430-3; Brosnan, et al., Br JAnaesth (2008) 101: 673-9; Mohammadi, et al., Eur J Pharmacol (2001)421: 85-91; Anderson, et al., J Med Chem (1997) 40: 1668-81; Brosnan, etal., Anesth Analg (2006) 103: 86-91). 87-96). Moreover, receptormutations that decrease ion channel sensitivity to conventionalanesthetics can also decrease sensitivity to nonconventional ones aswell (Yang, et al., Anesth Analg (2008) 106: 838-45), suggesting thesedisparate compounds all share a common nonspecific mechanism forinteracting with unrelated ion channels.

Second, the number of non-specific interfacial interactions should bedifferent between non-homologous channels. Hence, a prime determinant ofthe cut-off effect for ion channel modulation should be the watersolubility of a drug, and this threshold solubility cut-offconcentration should differ between ion channels from unrelatedsuperfamilies (e.g., 3-vs. 4-transmembrane receptors). Preliminary datasupports this contention (FIG. 9). In these studies, whole cell currentsof oocytes expressing either GABA_(A) (human α₁β₂γ_(2s)) receptors orNMDA (human NR1/rat NR2A) receptors were measured in the presence andabsence of saturated hydrocarbons with differing functional groups. Fora given homologous hydrocarbon series (with an identical functionalgroup), the agent solubility was varied by increasing the hydrocarbonchain length at the Ω-position. For example, the alkane series consistedof n-butane, n-pentane, and n-hexane; the alcohol series consisted of1-decanol and 1-dodecanol; the amines consisted of 1-octadecamine and1-eicosanamine; the ethers consisted of dipentylether and dihexylether;etc. All compounds studied were positive modulators (>10% increase overbaseline) of GABA_(A) receptors, but only compounds with a molar watersolubility greater than approximately 1 mM were also able to modulateNMDA receptors (>10% decrease from baseline), as shown in FIG. 9. Hence,water solubility correlated with specificity for GABA_(A) versus NMDAreceptors. This correlation is remarkably good since solubility valuesare calculated—not measured—for compounds in unbuffered pure waterinstead of the polyionic buffered solutions in which whole cell currentswere actually measured. Although increasing chain length increasesmolecular volume, the specificity cut-off was not associated with anyparticular hydrocarbon chain length. In addition, increasing chainlength also changes the activity of a hydrocarbon in solution; but therewas no correlation between saturated vapor pressure and the receptorspecificity cut-off.

Inhaled anesthetics enjoy widespread clinical use in general anesthesiain animals and humans, even though these drugs pose patient risks interms of cardiovascular and respiratory depression. Continued drugdevelopment is important to improving anesthetic safety. However, allvolatile anesthetics in clinical use were developed in the 1970s orbefore (Terrell, Anesthesiology (2008) 108: 531-3).

Creating newer and safer anesthetics requires knowledge of propertiesthat predict which receptors or receptor superfamilies are likely to bemodulated (Solt, et al., Curr Opin Anaesthesiol 2007; 20: 300-6). Dataare provided herein that demonstrate a threshold solubility related toNMDA versus GABA_(A) receptor specificity; analogous thresholdsolubility-specificity “cut-off” values exist for other receptors aswell. This is important, because actions at various receptors and ionchannels determine the pharmacologic profile of a drug. An inhaled agentthat selectively acts on NMDA receptors can offer increased analgesiaand autonomic quiescence, as do other injectable NMDA antagonists(Cahusac, et al., Neuropharmacology (1984) 23: 719-24; Bovill, et al.,Br J Anaesth (1971) 43: 496-9; Sanders, Br Med Bull (2004) 71: 115-35;France, et al., J Pharmacol Exp Ther (1989) 250: 197-201; Janig, et al.,J Auton Nerv Syst (1980) 2: 1-14; and Ness, et al., Brain Res 1988; 450:153-69). Drugs that act predominantly through certain GABA receptors canoffer excellent amnesia (Clark, et al., Arch Neurol (1979) 36: 296-300;Bonin, et al., Pharmacol Biochem Behav (2008) 90: 105-12; Cheng, et al.,J Neurosci 2006; 26: 3713-20; Sonner, et al., Mol Pharmacol (2005) 68:61-8; Vanini, et al., Anesthesiology (2008) 109: 978-88), but may alsocontribute to significant respiratory depression (Harrison, et al., Br JPharmacol 1985; 84: 381-91; Hedner, et al., J Neural Transm (1980) 49:179-86; Yamada, et al., Brain Res 1982; 248: 71-8; Taveira da Silva, etal., J Appl Physiol (1987) 62: 2264-72; Delpierre, et al., Neurosci Lett(1997) 226: 83-6; Li, et al., J Physiol (2006) 577: 307-18; Yang, J ApplPhysiol (2007) 102: 350-7). Other cut-off values may exist for receptorsthat cause negative inotropy and vasodilation, leading to cardiovascularinstability in anesthetized patients.

Knowledge of threshold cut-off values, and the means to easily predictthem through calculated estimates of a physical property facilitates therational design of new agents with an improved safety profile. Forexample, a good analgesic with poor immobilizing effects can be turnedinto a good general anesthetic by increasing the water solubility of theagent, such as by addition of an alcohol group or halogen, or by removalof long aliphatic chains that are not involved with high-affinitybinding interactions. Conversely, a good immobilizer could be altered toreduce water solubility in order eliminate certain side effects causedby receptor modulation above that cut-off value. It is also possible toalter activity at high affinity sites to make drugs less potent, therebyincreasing the drug ED50 and adding potentially desirablepharmacodynamic effects from low-affinity sites at these higherconcentrations.

The discovery of threshold solubility-specificity cut-off values allowsone to make predictions regarding anesthetic mechanisms. For example,since receptors with the same superfamily share sequence homology, theirsolubility cut-off values should be more similar to each other thanreceptors from different superfamilies.

II. Compounds for Effecting Anesthesia

a. Properties of the Present Inhalational Anesthetics

Using the water solubility threshold values to predict the efficacy andpharmacological activity of candidate compounds on anesthetic-sensitivereceptors, compounds for effecting anesthesia via delivery through therespiratory passages have been identified. Some of the compoundspotentiate GABA_(A) receptors without inhibiting NMDA receptors.Candidate compounds are selected based on their molar water solubility,vapor pressure, saline-gas partition coefficient, carbon-to-halogenratio, odor (or lack thereof), stability, e.g., in formulations forinhalational or pulmonary delivery, pharmacological activity ondifferent anesthetic-sensitive receptors, and toxicity.

i. Molar Water Solubility and Channel Cut-Off Values

Inhaled agents produce anesthesia via a summation of ion channel andcell membrane receptor effects that serve to decrease neuronalexcitability within the central nervous system. Anesthetic efficacy atspecific ion channels and cell membrane receptors is predicted by molarwater solubility. Hydrocarbons that have a molar water solubilitygreater than approximately 1.1 mM will modulate NMDA receptors whereasless soluble anesthetics will generally not, although there is smallvariability about this cut-off number with alcohols continuing tomodulate NMDA receptors at slightly lower solubility values and ethersexhibiting a cut-off effect at slightly higher solubility values.Conversely, inhaled hydrocarbons that cannot potentiate GABA_(A)receptors are not anesthetics. The water solubility cut-off for GABA_(A)receptor modulation is around 0.068 mM, but current data from ourlaboratory shows a 95% confidence interval that extends from 0.3 mM to0.016. These GABA_(A) solubility cut-off values provide an absolutemolar water solubility lower-limit for rapid database screening ofpotential anesthetic candidates. Inhaled agents less soluble than 0.068mM are unlikely to exhibit an anesthetic effect. Non-gaseous volatilecompounds more soluble than 100 mM are unlikely to have desirablepharmacokinetic properties, and this value serves as an upper solubilitylimit for database screening.

ii. Vapor Pressure

Inhaled anesthetics are administered via the respiratory system and thusneed a sufficiently high vapor pressure to facilitate rapid agentdelivery to a patient. The vapor pressure also must exceed anestheticpotency (a function of water and lipid solubility) for the agent to bedelivered via inhalation at 1 atmosphere pressure. For databasescreening, we selected a minimum vapor pressure of 0.1 atmospheres (76mmHg) at 25° C.

iii. Saline-Gas Partition Coefficient

Inhaled anesthetics with low Ostwald saline-gas partition coefficientsexhibit desirable and rapid washin and washout kinetics. These valuescan be estimated using previously published QSPR correlations, or byidentifying within a chemical family those compounds that exhibit highvapor pressure and low aqueous solubility which together suggest a lowOstwald saline-gas partition coefficient. Compounds should have asaline-gas partition coefficient ≤0.8 at 37° C.

iv. Carbon-to-Halogen Ratio

Modern anesthetics must be non-flammable in order to be clinicallyuseful.

Halogenation reduces flammability. Compounds for which the number ofhydrogen atoms did not exceed the number of carbon atoms are preferred.

v. Parent Compound Properties

1. Odor

Malodorous compounds will not be tolerated by patients or perioperativepersonnel.

Compounds containing thiols or sulfide linkages and primary andsecondary amine compounds have unpleasant odors, and so volatilecompounds containing these groups were excluded from screening.

2. Stability

Divalent bases (and sometimes monovalent bases) are used for CO₂absorption in anesthetic circuits; clinically-useful agents musttherefore be stable in the presence of strong bases. Compoundscontaining aldehyde, ketone, or carboxillic acid groups were unstable insoda lime are not preferred. Anesthetics should also be resistant tohydrolysis and redox reactions in vivo. Compounds with ester linkagescan be thermally unstable or hydrolysed by plasma and tissuecholinesterases; and those compounds resistant to hydrolysis may likelycause undesirable inhibition of these enzymes (which are essential formetabolism of other drugs). Therefore, compounds with ester linkages arenot preferred. Anesthetics with non-aromatic unsaturated carbon linkageshave been used historically (fluroxene, isopropenyl vinyl ether,trichloroethylene, vinethylene, ethylene) and shown to undergo extensivemetabolism that for some agents was associated with toxicity. Agentscontaining double or triple carbon bonds are not preferred.

3. Anesthetic-Sensitive Channel and Receptor Effects

Clinically-relevant anesthetics should inhibit excitatory ion channelsand cell receptors and potentiate inhibitory ion channels and cellreceptors. However, tests with unhalogenated compounds containingtertiary amines (4-methylmorpholine, N-methylpiperadine) caused directactivation of NMDA receptors which would be expected to antagonizeanesthetic effects and potentially cause neuronal injury at highconcentrations. Accordingly, compounds containing tertiary amines arenot preferred.

4. In Vitro and In Vivo Toxicity

Some parent structures (such as pyrrolidine) caused cytotoxicity duringoocyte electrophysiology studies. These compounds are not preferred.Other structures previously known to be highly toxic to animals orhumans (such as silanes and boranes) are not preferred.

b. Illustrative Anesthetics

Illustrative anesthetic compounds having the foregoing criteria includewithout limitation halogenated alcohol derivatives, halogenated diether(polyether) derivatives, halogenated dioxane derivatives, halogenateddioxolane derivatives, halogenated cyclopentane derivatives, halogenatedcyclohexane derivatives, halogenated tetrahydrofuran derivatives, andhalogenated tetrahydropyran derivatives. The compounds can be formulatedfor delivery to a subject via the respiratory pathways, e.g., forinhalational or pulmonary delivery.

The compounds described herein may form salts with acids, and such saltsare included in the present invention. In one embodiment, the salts arepharmaceutically acceptable salts. The term “salts” embraces additionsalts of free acids that are useful within the methods of the invention.The term “pharmaceutically acceptable salt” refers to salts that possesstoxicity profiles within a range that affords utility in pharmaceuticalapplications.

Pharmaceutically unacceptable salts may nonetheless possess propertiessuch as high crystallinity, which have utility in the practice of thepresent invention, such as for example utility in process of synthesis,purification or formulation of compounds useful within the methods ofthe invention.

Suitable pharmaceutically acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of inorganicacids include sulfate, hydrogen sulfate, hydrochloric, hydrobromic,hydriodic, nitric, carbonic, sulfuric, and phosphoric acids (includinghydrogen phosphate and dihydrogen phosphate), Appropriate organic acidsmay be selected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which include formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric,salicylic, galactaric and galacturonic acid.

Suitable pharmaceutically acceptable base addition salts of compounds ofthe invention include, for example, metallic salts including alkalimetal, alkaline earth metal and transition metal salts such as, forexample, calcium, magnesium, potassium, sodium and zinc salts,pharmaceutically acceptable base addition salts also include organicsalts made from basic amines such as, for example,N,N′-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. All ofthese salts may be prepared from the corresponding compound by reacting,for example, the appropriate acid or base with the compound.

Some of the compounds set forth herein include chiral centers. Chiralcenters generally refer to a carbon atom that is attached to four uniquesubstituents. With respect to these chiral-center containing compounds,the present invention provides for methods that include the use of, andadministration of, these chiral-center containing compounds as eitherpure entantiomers, as mixtures of enantiomers, as well as mixtures ofdiastereoisomers or as a purified diastereomer. In some embodiments, theR configuration of a particular enantiomer is preferred for a particularmethod. In yet other embodiments, the S configuration of a particularenantiomer is preferred for a particular method. The present inventionincludes methods of administering racemic mixtures of compounds havingchiral centers. The present invention includes methods of administeringone particular stereoisomer of a compound. In certain embodiments, aparticular ratio of one enantiomer to another enantiomer is preferredfor use with a method described herein. In other embodiments, aparticular ratio of one diastereomer to other diastereomers is preferredfor use with a method described herein.

i. Halogenated Alcohol Derivatives

Illustrative halogenated alcohol derivatives include without limitationa compound or a mixture of compounds of Formula I:

-   -   wherein:    -   n is 0-4,    -   R¹ is H;    -   R², R³, R⁴, R⁵ and R⁶ independently are selected from H, X, CX₃,        CHX₂, CH₂X and C₂X₅; and    -   wherein X is a halogen, the compound having vapor pressure of at        least 0.1 atmospheres (76 mmHg) at 25° C., and the number of        hydrogen atoms in Formula I do not exceed the number of carbon        atoms, thereby inducing anesthesia in the subject. In various        embodiments, X is a halogen selected from the group consisting        of F, Cl, Br and I. In some embodiments, X is F. In some        embodiments, le is selected from H, CHFOH, CHFOH and CF₂OH,        CHClOH, CCl₂OH and CFClOH. In some embodiments, R², R³, R⁴, R⁵        and R⁶ independently are selected from H, F, Cl, Br, I, CF₃,        CHF₂, CH₂F, C₂F₅, CCl₃, CHCl₂, CH₂Cl, C₂Cl₅, CCl₂F, CClF₂,        CHClF, C₂ClF₄, C₂Cl₂F₃, C₂Cl₃F₂, and C₂Cl₄F.

In some embodiments, the halogenated alcohol derivatives are selectedfrom the group consisting of:

-   a) Methanol, 1-fluoro-1-[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]-    (CAS #1351959-82-4);-   b) 1-Butanol, 4,4,4-trifluoro-3,3-bis(trifluoromethyl)- (CAS    #14115-49-2);-   c) 1-Butanol, 1,1,2,2,3,3,4,4,4-nonafluoro- (CAS #3056-01-7);-   d) 1-Butanol, 2,2,3,4,4,4-hexafluoro-3-(trifluoromethyl)- (CAS    #782390-93-6);-   e) 1-Butanol, 3,4,4,4-tetrafluoro-3-(trifluoromethyl)- (CAS    #90999-87-4);-   f) 1-Pentanol, 1,1,4,4,5,5,5-heptafluoro- (CAS #313503-66-1); and-   g) 1-Pentanol, 1,1,2,2,3,3,4,4,5,5,5-undecafluoro- (CAS    #57911-98-5).

In some other embodiments, the halogenated alcohol derivatives areselected from the group consisting of:

-   a) 2-Pentanol, 1,1,1,3,3,5,5,5-octafluoro-2-(trifluoromethyl)- (CAS    #144475-50-3);-   b) 2-Pentanol,    1,1,1,3,4,5,5,5-octafluoro-4-(trifluoromethyl)-(2R,3S)- (CAS    #126529-27-9);-   c) 2-Pentanol, 1,1,1,3,4,4,5,5,5-nonafluoro-, (2R,3S)-rel- (CAS    #126529-24-6);-   d) 2-Pentanol,    1,1,1,3,4,5,5,5-octafluoro-4-(trifluoromethyl)-(2R,3R)- (CAS    #126529-17-7);-   e) 2-Pentanol, 1,1,1,3,4,4,5,5,5-nonafluoro-, (2R,3R)-rel- (CAS    #126529-14-4);-   f) 1-Butanol, 1,1,2,2,3,3,4,4-octafluoro- (CAS #119420-27-8);-   g) 1-Butanol, 2,3,3,4,4,4-hexafluoro-2-(trifluoromethyl)- (CAS    #111736-92-6);-   h) 2-Pentanol, 1,1,1,3,3,4,5,5,5-nonafluoro-, (R*,S*)- (9CI) (CAS    #99390-96-2);-   i) 2-Pentanol, 1,1,1,3,3,4,5,5,5-nonafluoro-, (R*,R*)- (9CI) (CAS    #99390-90-6);-   j) 2-Pentanol, 1,1,1,3,3,4,4,5,5,5-decafluoro-2-(trifluoromethyl)-    (CAS #67728-22-7);-   k) 1-Pentanol, 1,1,2,2,3,3,4,4,5,5,5-undecafluoro- (CAS    #57911-98-5);-   l) 2-Pentanol, 1,1,1,3,3,4,4,5,5,5-decafluoro- (CAS #377-53-7);-   m) 1-Pentanol, 2,2,3,4,4,5,5,5-octafluoro- (CAS #357-35-7);-   n) 1-Butanol, 2,3,4,4,4-pentafluoro-2-(trifluoromethyl)- (CAS    #357-14-2);-   o) 1-Pentanol, 2,2,3,3,4,4,5,5,5-nonafluoro (CAS #355-28-2);-   p) 1-Butanol, 2,3,4,4,4-pentafluoro-2-(trifluoromethyl)-,(R*,S*)-    (9CI) (CAS #180068-23-9);-   q) 1-Butanol, 2,3,4,4,4-pentafluoro-2-(trifluoromethyl)-(R*,R*)-    (9CI) (CAS #180068-22-8);-   r) 2-Butanol, 1,1,1,3,3-pentafluoro-2-(trifluoromethyl)- (CAS    #144444-16-6);-   s) 2-Butanol, 1,1,1,3,3,4,4,4-octafluoro (CAS #127256-73-9);-   t) 1-Butanol, 2,2,3,4,4,4-hexafluoro-3-(trifluoromethyl)- (CAS    #782390-93-6);-   u) 2-Propanol, 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)- (CAS    #2378-02-01);-   v) 1-Hexanol, 1,1,2,2,3,3,4,4,5,5-decafluoro (CAS #1118030-44-6);-   w) 1-Hexanol, 1,1,2,2,3,3,4,4,5,5,6,6-dodecafluoro- (CAS    #119420-28-9);-   x) 1-Hexanol, 1,1,2,2,3,3,4,4,5,5,6,6,6-tridecafluoro- (CAS    #7057-81-0);-   y) 1-Hexanol, 3,3,4,4,5,5,6,6,6-nonafluoro- (CAS #2043-47-2);-   z) 1-Hexanol, 2,2,3,3,4,4,5,5,6,6,6-undecafluoro- (CAS #423-46-1);-   aa) 1-Hexanol, 2,2,3,4,4,5,5,6,6,6-decafluoro- (CAS #356-25-2);-   ab) 1-Heptanol, 3,3,4,4,5,5,6,6,7,7,7-undecafluoro- (CAS    #185689-57-0);-   ac) 1-Hexanol, 2,2,3,3,4,4,5,6,6,6-decafluoro-5-(trifluoromethyl)-    (CAS #849819-50-7);-   ad) 1-Hexanol, 2,2,3,3,4,4,5,6,6,6-decafluoro-5-(trifluoromethyl)-    (CAS #89076-11-9);-   ae) 1-Hexanol,    2,2,3,4,4,6,6,6-octafluoro-3,5,5-tris(trifluoromethyl)- (CAS    #232267-34-4);-   af) 1-Hexanol, 2,2,3,4,4,5,6,6,6-nonafluoro-3-(trifluoromethyl)-    (CAS #402592-21-6);-   ag) 1-Hexanol, 4,5,5,6,6,6-hexafluoro-4-(trifluoromethyl)- (CAS    #239463-96-8); and-   ah) 1-Hexanol, 4,4,5,5,6,6,6-heptafluoro-3,3-bis(trifluoromethyl)-    (CAS #161261-12-7).

In some embodiments, the above-described halogenated alcohol derivativesare useful as inhaled sedatives, also as inhaled tranquilizers, also asinhaled analgesics, and also as inhaled hypnotics. In some embodiments,the halogenated alcohol derivatives set forth herein are useful asinhaled sedatives. In some embodiments, the halogenated alcoholderivatives set forth herein are useful as inhaled tranquilizers. Insome embodiments, the halogenated alcohol derivatives set forth hereinare useful as inhaled analgesics. In some embodiments, the halogenatedalcohol derivatives set forth herein are useful as inhaled hypnotics. Insome embodiments, the halogenated alcohol derivatives set forth hereinare useful as tranquilizers. In some embodiments, the halogenatedalcohol derivatives set forth herein are useful as analgesics. In someembodiments, the halogenated alcohol derivatives set forth herein areuseful as hypnotics.

In some specific embodiments, the halogenated alcohol derivative isselected from 1-Hexanol,2,2,3,3,4,4,5,6,6,6-decafluoro-5-(trifluoromethyl)- (CAS #89076-11-9).1-Hexanol, 2,2,3,3,4,4,5,6,6,6-decafluoro-5-(trifluoromethyl)- wasobserved to be useful as a GABA-A receptor agonist and a weak NMDAreceptor antagonist at saturating aqueous phase concentrations. Thepresent invention includes methods of administering 1-Hexanol,2,2,3,3,4,4,5,6,6,6-decafluoro-5-(trifluoromethyl)- in order to inducesedative or hypnotic states in a subject or patient.

ii. Halogenated Diether (Polyether) Derivatives

Illustrative halogenated diether (polyether derivatives) include withoutlimitation a compound or a mixture of compounds of Formula II:

-   -   wherein:    -   n is 1-3,    -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ independently are selected        from H, X, CX₃, CHX₂, CH₂X and C₂X₅; and    -   wherein X is a halogen, the compound having vapor pressure of at        least 0.1 atmospheres (76 mmHg) at 25° C., and the number of        hydrogen atoms in Formula II do not exceed the number of carbon        atoms, thereby inducing anesthesia in the subject. In various        embodiments, X is a halogen selected from the group consisting        of F, Cl, Br and I. In some embodiments, X is F. In some        embodiments, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ independently are        selected from H, F, Cl, Br, I, CF₃, CHF₂, CH₂F, C₂F₅, CCl₃,        CHCl₂, CH₂Cl, C₂Cl₅, CCl₂F, CClF₂, CHClF, C₂ClF₄, C₂Cl₂F₃,        C₂Cl₃F₂, and C₂Cl₄F.

In some embodiments, the halogenated diether (polyether derivatives) areselected from the group consisting of:

-   a) Ethane, 1,1,2-trifluoro-1,2-bis(trifluoromethoxy)- (CAS    #362631-92-3);-   b) Ethane, 1,1,1,2-tetrafluoro-2,2-bis(trifluoromethoxy)- (CAS    #115395-39-6);-   c) Ethane,    1-(difluoromethoxy)-1,1,2,2-tetrafluoro-2-(trifluoromethoxy)- (CAS    #40891-98-3);-   d) Ethane, 1,1,2,2-tetrafluoro-1,2-bis(trifluoromethoxy)- (CAS    #378-11-0);-   e) Ethane, 1,2-difluoro-1,2-bis(trifluoromethoxy)- (CAS    #362631-95-6);-   f) Ethane, 1,2-bis(trifluoromethoxy)- (CAS #1683-90-5);-   g) Propane, 1,1,3,3-tetrafluoro-1,3-bis(trifluoromethoxy)- (CAS    #870715-97-2);-   h) Propane, 2,2-difluoro-1,3-bis(trifluoromethoxy)- (CAS    #156833-18-0);-   i) Propane, 1,1,1,3,3-pentafluoro-3-methoxy-2-(trifluoromethoxy)-    (CAS #133640-19-4;-   j) Propane, 1,1,1,3,3,3-hexafluoro-2-(fluoromethoxymethoxy)- (CAS    #124992-92-3); and-   k) Propane, 1,1,1,2,3,3-hexafluoro-3-methoxy-2-(trifluoromethoxy)-    (CAS #104159-55-9).

iii. Halogenated Dioxane Derivatives

Illustrative halogenated dioxane derivatives include without limitationa compound or a mixture of compounds of Formula III:

-   -   wherein:    -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ independently are selected        from H, X, CX₃, CHX₂, CH₂X and C₂X₅; and    -   wherein X is a halogen, the compound has a vapor pressure of at        least 0.1 atmospheres (76 mmHg) at 25° C., and the number of        hydrogen atoms of Formula III do not exceed the number of carbon        atoms, thereby inducing anesthesia in the subject. In various        embodiments, X is a halogen selected from the group consisting        of F, Cl, Br and I. In some embodiments, X is F. In some        embodiments, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ independently are        selected from H, F, Cl, Br, I, CF₃, CHF₂, CH₂F, C₂F₅, CCl₃,        CHCl₂, CH₂Cl, C₂Cl₅, CCl₂F, CClF₂, CHClF, C₂ClF₄, C₂Cl₂F₃,        C₂Cl₃F₂, and C₂Cl₄F.

In some embodiments, the halogenated dioxane derivatives are selectedfrom the group consisting of:

-   a) 1,4-Dioxane, 2,2,3,3,5,6-hexafluoro- (CAS #362631-99-0);-   b) 1,4-Dioxane, 2,3-dichloro-2,3,5,5,6,6-hexafluoro- (CAS    #135871-00-0);-   c) 1,4-Dioxane, 2,3-dichloro-2,3,5,5,6,6-hexafluoro-, trans- (9CI)    (CAS #56625-45-7);-   d) 1,4-Dioxane, 2,3-dichloro-2,3,5,5,6,6-hexafluoro-, cis- (9CI)    (CAS #56625-44-6);-   e) 1,4-Dioxane, 2,2,3,5,6,6-hexafluoro- (CAS #56269-26-2);-   f) 1,4-Dioxane, 2,2,3,5,5,6-hexafluoro- (CAS #56269-25-1);-   g) 1,4-Dioxane, 2,2,3,3,5,6-hexafluoro-, trans- (9CI) (CAS    #34206-83-2);-   h) 1,4-Dioxane, 2,2,3,5,5,6-hexafluoro-, cis- (9CI) (CAS    #34181-52-7);-   i) p-Dioxane, 2,2,3,5,5,6-hexafluoro-, trans- (8CI) (CAS    #34181-51-6);-   j) 1,4-Dioxane, 2,2,3,5,6,6-hexafluoro-, cis- (9CI) (CAS    #34181-50-5);-   k) p-Dioxane, 2,2,3,5,6,6-hexafluoro-, trans- (8CI) (CAS    #34181-49-2);-   l) 1,4-Dioxane, 2,2,3,3,5,6-hexafluoro-, (5R,6S)-rel- (CAS    #34181-48-1);-   m) 1,4-Dioxane, 2,2,3,3,5,5,6-heptafluoro- (CAS #34118-18-8); and-   n) 1,4-Dioxane, 2,2,3,3,5,5,6,6-octafluoro- (CAS #32981-22-9).

iv. Halogenated Dioxolane Derivatives

Illustrative halogenated dioxolane derivatives include withoutlimitation a compound or a mixture of compounds of Formula IV:

-   -   wherein:    -   R¹, R², R³, R⁴, R⁵ and R⁶ independently are selected from H, X,        CX₃, CHX₂, CH₂X and C₂X₅; and    -   wherein X is a halogen, the compound has a vapor pressure of at        least 0.1 atmospheres (76 mmHg) at 25° C., and the number of        hydrogen atoms of Formula IV do not exceed the number of carbon        atoms, thereby inducing anesthesia in the subject. In various        embodiments, X is a halogen selected from the group consisting        of F, Cl, Br and I. In some embodiments, X is F. In some        embodiments, R¹, R², R³, R⁴, R⁵ and R⁶ independently are        selected from H, F, Cl, Br, I, CF₃, CHF₂, CH₂F, C₂F₅, CCl₃,        CHCl₂, CH₂Cl, C₂Cl₅, CCl₂F, CClF₂, CHClF, C₂ClF₄, C₂Cl₂F₃,        C₂Cl₃F₂, and C₂Cl₄F.

In some embodiments, the halogenated dioxolane derivatives are selectedfrom the group consisting of:

-   a) 1,3-Dioxolane, 2,4,4,5-tetrafluoro-5-(trifluoromethyl)- (CAS    #344303-08-8);-   b) 1,3-Dioxolane, 2-chloro-4,4,5-trifluoro-5-(trifluoromethyl)- (CAS    #344303-05-5);-   c) 1,3-Dioxolane, 4,4,5,5-tetrafluoro-2-(trifluoromethyl)- (CAS    #269716-57-6);-   d) 1,3-Dioxolane, 4-chloro-2,2,4-trifluoro-5-(trifluoromethyl)- (CAS    #238754-29-5);-   e) 1,3-Dioxolane, 4,5-dichloro-2,2,4,5-tetrafluoro-, trans- (9CI)    (CAS #162970-78-7);-   f) 1,3-Dioxolane, 4,5-dichloro-2,2,4,5-tetrafluoro-, cis- (9CI) (CAS    #162970-76-5);-   g) 1,3-Dioxolane, 4-chloro-2,2,4,5,5-pentafluoro- (CAS    #139139-68-7);-   h) 1,3-Dioxolane, 4,5-dichloro-2,2,4,5-tetrafluoro- (CAS    #87075-00-1);-   i) 1,3-Dioxolane, 2,4,4,5-tetrafluoro-5-(trifluoromethyl)-, trans-    (9CI) (CAS #85036-66-4);-   j) 1,3-Dioxolane, 2,4,4,5-tetrafluoro-5-(trifluoromethyl)-, cis-    (9CI) (CAS #85036-65-3);-   k) 1,3-Dioxolane, 2-chloro-4,4,5-trifluoro-5-(trifluoromethyl)-,    trans- (9CI) (CAS #85036-60-8);-   l) 1,3-Dioxolane, 2-chloro-4,4,5-trifluoro-5-(trifluoromethyl)-,    cis- (9CI) (CAS #85036-57-3);-   m) 1,3-Dioxolane, 2,2-dichloro-4,4,5,5-tetrafluoro- (CAS    #85036-55-1);-   n) 1,3-Dioxolane, 4,4,5-trifluoro-5-(trifluoromethyl)- (CAS    #76492-99-4);-   o) 1,3-Dioxolane, 4,4-difluoro-2,2-bis(trifluoromethyl)- (CAS    #64499-86-1);-   p) 1,3-Dioxolane, 4,5-difluoro-2,2-bis(trifluoromethyl)-, cis- (9CI)    (CAS #64499-85-0);-   q) 1,3-Dioxolane, 4,5-difluoro-2,2-bis(trifluoromethyl)-, trans-    (9CI) (CAS #64499-66-7);-   r) 1,3-Dioxolane, 4,4,5-trifluoro-2,2-bis(trifluoromethyl)- (CAS    #64499-65-6);-   s) 1,3-Dioxolane, 2,4,4,5,5-pentafluoro-2-(trifluoromethyl)- (CAS    #55135-01-8);-   t) 1,3-Dioxolane, 2,2,4,4,5,5-hexafluoro- (CAS #21297-65-4); and-   u) 1,3-Dioxolane, 2,2,4,4,5-pentafluoro-5-(trifluoromethyl)- (CAS    #19701-22-5).

v. Halogenated Cyclopentane Derivatives

Illustrative halogenated cyclopentane derivatives include withoutlimitation a compound or a mixture of compounds of Formula V:

-   -   wherein:    -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ independently are        selected from H, X, CX₃, CHX₂, CH₂X and C₂X₅; and    -   wherein X is a halogen, the compound has a vapor pressure of at        least 0.1 atmospheres (76 mmHg) at 25° C., and the number of        hydrogen atoms of Formula V do not exceed the number of carbon        atoms, thereby inducing anesthesia in the subject. In various        embodiments, X is a halogen selected from the group consisting        of F, Cl, Br and I. In some embodiments, X is F. In some        embodiments, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰        independently are selected from H, F, Cl, Br, I, CF₃, CHF₂,        CH₂F, C₂F₅, CCl₃, CHCl₂, CH₂Cl, C₂Cl₅, CCl₂F, CClF₂, CHClF,        C₂ClF₄, C₂Cl₂F₃, C₂Cl₃F₂, and C₂Cl₄F.

In some embodiments, the halogenated cyclopentane derivatives areselected from the group consisting of:

-   a) Cyclopentane, 5-chloro-1,1,2,2,3,3,4,4-octafluoro- (CAS    #362014-70-8);-   b) Cyclopentane, 1,1,2,2,3,4,4,5-octafluoro- (CAS #773-17-1);-   c) Cyclopentane, 1,1,2,2,3,3,4,5-octafluoro- (CAS #828-35-3);-   d) Cyclopentane, 1,1,2,3,3,4,5-heptafluoro- (CAS #3002-03-7);-   e) Cyclopentane, 1,1,2,2,3,3,4,4-octafluoro- (CAS #149600-73-7);-   f) Cyclopentane, 1,1,2,2,3,4,5-heptafluoro- (CAS #1765-23-7);-   g) Cyclopentane, 1,1,2,3,4,5-hexafluoro- (CAS #699-38-7);-   h) Cyclopentane, 1,1,2,2,3,3,4-heptafluoro- (CAS #15290-77-4);-   i) Cyclopentane, 1,1,2,2,3,4-hexafluoro- (CAS #199989-36-1);-   j) Cyclopentane, 1,1,2,2,3,3-hexafluoro- (CAS #123768-18-3); and-   k) Cyclopentane, 1,1,2,2,3-pentafluoro- (CAS #1259529-57-1).

In some embodiments, the halogenated cyclopentane derivatives areselected from the group consisting of:

-   c) Cyclopentane, 1,1,2,2,3,3,4,5-octafluoro- (CAS #828-35-3);-   e) Cyclopentane, 1,1,2,2,3,3,4,4-octafluoro- (CAS #149600-73-7); and-   h) Cyclopentane, 1,1,2,2,3,3,4-heptafluoro- (CAS #15290-77-4).

In some embodiments, the compound administered, or used with any of themethods set forth herein, is 1,1,2,2,3,3,4,5-octafluorocyclopentane. Incertain embodiments, the compound has the structure selected from thegroup consisting of

In certain embodiments, the compound administered, or used with any ofthe methods set forth herein, is selected from the group consisting of(4R,5S)-1,1,2,2,3,3,4,5-octafluorocyclopentane,(4S,5S)-1,1,2,2,3,3,4,5-octafluorocyclopentane, and(4R,5R)-1,1,2,2,3,3,4,5-octafluorocyclopentane. Mixtures of(4R,5S)-1,1,2,2,3,3,4,5-octafluorocyclopentane,(4S,5S)-1,1,2,2,3,3,4,5-octafluorocyclopentane, and(4R,5R)-1,1,2,2,3,3,4,5-octafluorocyclopentane may be used with themethods set forth herein. The present invention also includesadministering, or using with any of the methods set forth herein, aparticular stereoisomer of 1,1,2,2,3,3,4,5-octafluorocyclopentane, e.g.,(4R,5S)-1,1,2,2,3,3,4,5-octafluorocyclopentane, or(4S,5S)-1,1,2,2,3,3,4,5-octafluorocyclopentane, or(4R,5R)-1,1,2,2,3,3,4,5-octafluorocyclopentane.

In some embodiments, the compound administered, or used with any of themethods set forth herein, is 1,1,2,2,3,3,4-heptafluorocyclopentane (CAS#15290-77-4). In certain embodiments, the compound has the structureselected from the group consisting of

In certain embodiments, the compound administered, or used with any ofthe methods set forth herein, is selected from the group consisting of(R)-1,1,2,2,3,3,4-heptafluorocyclopentane and(S)-1,1,2,2,3,3,4-heptafluorocyclopentane. Mixtures, e.g., racemicmixtures, of (R)-1,1,2,2,3,3,4-heptafluorocyclopentane and(S)-1,1,2,2,3,3,4-heptafluorocyclopentane may be used with the methodsset forth herein. The present invention also includes administering, orusing with any of the methods set forth herein, a particularstereoisomer of 1,1,2,2,3,3,4-heptafluorocyclopentane (CAS #15290-77-4),e.g., (R)-1,1,2,2,3,3,4-heptafluorocyclopentane or(S)-1,1,2,2,3,3,4-heptafluorocyclopentane.

vi. Halogenated Cyclohexane Derivatives

An illustrative halogenated cyclohexane derivative includes withoutlimitation 1,1,2,2,3,3,4,4-octafluoro-cyclohexane (CAS #830-15-9).

vii. Halogenated Tetrahydrofuran Derivatives

Illustrative halogenated tetrahydrofuran derivatives include withoutlimitation a compound or a mixture of compounds of Formula VI:

-   -   wherein:    -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ independently are selected        from H, X, CX₃, CHX₂, CH₂X and C₂X₅; and    -   wherein X is a halogen, the compound has a vapor pressure of at        least 0.1 atmospheres (76 mmHg) at 25° C., and the number of        hydrogen atoms of Formula VI do not exceed the number of carbon        atoms, thereby inducing anesthesia in the subject. In various        embodiments, X is a halogen selected from the group consisting        of F, Cl, Br and I. In some embodiments, X is F. In some        embodiments, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ independently are        selected from H, F, Cl, Br, I, CF₃, CHF₂, CH₂F, C₂F₅, CCl₃,        CHCl₂, CH₂Cl, C₂Cl₅, CCl₂F, CClF₂, CHClF, C₂ClF₄, C₂Cl₂F₃,        C₂Cl₃F₂, and C₂Cl₄F.

In some embodiments, the halogenated tetrahydrofuran derivatives areselected from the group consisting of:

-   a) Furan, 2,3,4,4-tetrafluorotetrahydro-2,3-bis(trifluoromethyl)-    (CAS #634191-25-6);-   b) Furan, 2,2,3,3,4,4,5-heptafluorotetrahydro-5-(trifluoromethyl)-    (CAS #377-83-3);-   c) Furan, 2,2,3,3,4,5,5-heptafluorotetrahydro-4-(trifluoromethyl)-    (CAS #374-53-8);-   d) Furan, 2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,    (2a,3β,4a)- (9CI) (CAS #133618-53-8);-   e) Furan, 2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,    (2a,3a,4β)- (CAS #133618-52-7);-   f) Furan, 2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,    (2a,3β,4a)- (9CI) (CAS #133618-53-8);-   g) Furan, 2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-,    (2α,3α,4β)- (9CI) (CAS #133618-52-7);-   h) Furan, 2,2,3,3,5,5-hexafluorotetrahydro-4-(trifluoromethyl)- (CAS    #61340-70-3);-   i) Furan, 2,3-difluorotetrahydro-2,3-bis(trifluoromethyl)- (CAS    #634191-26-7);-   j) Furan, 2-chloro-2,3,3,4,4,5,5-heptafluorotetrahydro- (CAS    #1026470-51-8);-   k) Furan, 2,2,3,3,4,4,5-heptafluorotetrahydro-5-methyl- (CAS    #179017-83-5);-   l) Furan, 2,2,3,3,4,5-hexafluorotetrahydro-5-(trifluoromethyl)-,    trans- (9CI) (CAS #133618-59-4); and-   m) Furan, 2,2,3,3,4,5-hexafluorotetrahydro-5-(trifluoromethyl)-,    cis- (9CI) (CAS #133618-49-2).

viii. Halogenated Tetrahydropyran Derivatives

Illustrative halogenated tetrahydropyran derivatives include withoutlimitation a compound or a mixture of compounds of Formula VII:

-   -   wherein:    -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ independently are        selected from H, X, CX₃, CHX₂, CH₂X, and C₂X₅; and    -   wherein X is a halogen, the compound has a vapor pressure of at        least 0.1 atmospheres (76 mmHg) at 25° C., and the number of        hydrogen atoms of Formula VII do not exceed the number of carbon        atoms, thereby inducing anesthesia in the subject. In various        embodiments, X is a halogen selected from the group consisting        of F, Cl, Br and I. In some embodiments, X is F. In some        embodiments, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰        independently are selected from H, F, Cl, Br, I, CF₃, CHF₂,        CH₂F, C₂F₅, CCl₃, CHCl₂, CH₂Cl, C₂Cl₅, CCl₂F, CClF₂, CHClF,        C₂ClF₄, C₂Cl₂F₃, C₂Cl₃F₂, and C₂Cl₄F.

In some embodiments, the halogenated tetrahydropyran derivatives areselected from the group consisting of:

-   a) 2H-Pyran, 2,2,3,3,4,5,5,6,6-nonafluorotetrahydro-4- (CAS    #71546-79-7);-   b) 2H-Pyran,    2,2,3,3,4,4,5,5,6-nonafluorotetrahydro-6-(trifluoromethyl)- (CAS    #356-47-8);-   c) 2H-Pyran,    2,2,3,3,4,4,5,6,6-nonafluorotetrahydro-5-(trifluoromethyl)- (CAS    #61340-74-7);-   d) 2H-Pyran, 2,2,6,6-tetrafluorotetrahydro-4-(trifluoromethyl)- (CAS    #657-48-7);-   e) 2H-Pyran, 2,2,3,3,4,4,5,5,6-nonafluorotetrahydro-6-methyl- (CAS    #874634-55-6);-   f) Perfluorotetrahydropyran (CAS #355-79-3);-   g) 2H-Pyran, 2,2,3,3,4,5,5,6-octafluorotetrahydro-, (4R,6S)-rel-    (CAS #362631-93-4); and-   h) 2H-Pyran, 2,2,3,3,4,4,5,5,6-nonafluorotetrahydro- (CAS    #65601-69-6).

III. Subjects Who May Benefit

The anesthetic compounds and methods described herein find use forinducing anesthesia in any subject in need thereof. For example, thesubject may be undergoing a surgical procedure that requires theinduction of temporary unconsciousness and/or immobility.

The patient receiving the anesthetic may have been selected for havingor at risk of having a sensitivity or adverse reaction to an anestheticthat activates a particular anesthetic-sensitive receptor or subset ofanesthetic-receptors. For example, the patient may have or be at risk ofhaving a sensitivity or adverse reaction to an anesthetic that activatesone or more of NMDA receptors, two-pore potassium channels,voltage-gated ion channels, GABA receptors, glycine receptors, oranother anesthetic-sensitive receptor. In such cases, the anestheticadministered to the patient has a water solubility that is less than thesolubility threshold concentration for the receptor for which it issought to avoid modulating.

In various embodiments, it may be desirable to induce in the subjectamnesia and/or immobility by potentiating GABA_(A) receptors, butminimize or avoid inducing possible respiratory or neurologicside-effects that may be associated with inhibition of NMDA receptors.

IV. Formulation and Administration

a. Formulation

The invention also encompasses the use of pharmaceutical compositionscomprising a compound or a mixture of compounds (e.g., of Formula I,Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VIIand/or Formula VIII, as described herein), or salts thereof, to induceanesthesia in a subject.

Such a pharmaceutical composition may consist of at least one compoundof the invention or a salt thereof, in a form suitable foradministration to a subject, or the pharmaceutical composition maycomprise at least one compound of the invention or a salt thereof, andone or more pharmaceutically acceptable carriers, one or more additionalingredients, or some combination of these. The at least one compound ofthe invention may be present in the pharmaceutical composition in theform of a physiologically acceptable salt, such as in combination with aphysiologically acceptable cation or anion, as is well known in the art.

The relative amounts of the active ingredient, the pharmaceuticallyacceptable carrier, and any additional ingredients in a pharmaceuticalcomposition of the invention will vary, depending upon the identity,size, and condition of the subject treated and further depending uponthe route by which the composition is to be administered. By way ofexample, the composition may comprise between 0.1% and 100% (w/w) activeingredient.

As used herein, the term “pharmaceutically acceptable carrier” means apharmaceutically acceptable material, composition or carrier, such as aliquid or solid filler, stabilizer, dispersing agent, suspending agent,diluent, excipient, thickening agent, solvent or encapsulating material,involved in carrying or transporting a compound useful within theinvention within or to the subject such that it may perform its intendedfunction. Typically, such constructs are carried or transported from oneorgan, or portion of the body, to another organ, or portion of the body.Each carrier must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation, including the compound usefulwithin the invention, and not injurious to the subject. Some examples ofmaterials that may serve as pharmaceutically acceptable carriersinclude: sugars, such as lactose, glucose and sucrose; starches, such ascorn starch and potato starch; cellulose, and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients, such as cocoabutter and suppository waxes; oils, such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols, such as glycerin, sorbitol, mannitoland polyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; surface active agents; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffersolutions; and other non-toxic compatible substances employed inpharmaceutical formulations. As used herein, “pharmaceuticallyacceptable carrier” also includes any and all coatings, antibacterialand antifungal agents, and absorption delaying agents, and the like thatare compatible with the activity of the compound useful within theinvention, and are physiologically acceptable to the subject.Supplementary active compounds may also be incorporated into thecompositions. The “pharmaceutically acceptable carrier” may furtherinclude a pharmaceutically acceptable salt of the compound useful withinthe invention. Other additional ingredients that may be included in thepharmaceutical compositions used in the practice of the invention areknown in the art and described, for example in Remington: The Scienceand Practice of Pharmacy (Remington: The Science & Practice ofPharmacy), 21^(st) Edition, 2011, Pharmaceutical Press, and Ansel'sPharmaceutical Dosage Forms and Drug Delivery Systems, Allen, et al.,eds., 9^(th) Edition, 2010, Lippincott Williams & Wilkins, which areincorporated herein by reference.

In various embodiments, the compounds are formulated for delivery via arespiratory pathway, e.g., suitably developed for inhalational,pulmonary, intranasal, delivery. In various embodiments, the compound ormixture of compounds is vaporized into or directly mixed or diluted witha carrier gas, e.g., oxygen, air, or helium, or a mixture thereof. Apreservative may be further included in the vaporized formulations, asappropriate. Other contemplated formulations include projectednanoparticles, and liposomal preparations. The route(s) ofadministration will be readily apparent to the skilled artisan and willdepend upon any number of factors including the type and severity of thedisease being treated, the type and age of the veterinary or humanpatient being treated, and the like.

The formulations of the pharmaceutical compositions described herein maybe prepared by any method known or hereafter developed in the art ofpharmacology. In general, such preparatory methods include the step ofbringing the active ingredient into association with a carrier or one ormore other accessory ingredients, and then, if necessary or desirable,shaping or packaging the product into a desired single- or multi-doseunit.

As used herein, a “unit dose” is a discrete amount of the pharmaceuticalcomposition comprising a predetermined amount of the active ingredient.The amount of the active ingredient is generally equal to the dosage ofthe active ingredient that would be administered to a subject or aconvenient fraction of such a dosage such as, for example, one-half orone-third of such a dosage. The unit dosage form may be for a singledaily dose or one of multiple daily doses (e.g., about 1 to 4 or moretimes per day). When multiple daily doses are used, the unit dosage formmay be the same or different for each dose.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for ethical administration to humans, it will be understood bythe skilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and perform such modification with merely ordinary, if any,experimentation. Subjects to which administration of the pharmaceuticalcompositions of the invention is contemplated include, but are notlimited to, humans and other primates, mammals including commerciallyrelevant mammals including agricultural mammals (e.g., cattle, pigs,horses, sheep), domesticated mammals (e.g., cats, and dogs), andlaboratory mammals (e.g., rats, mice, rabbits, hamsters).

b. Administration

In some embodiments, the methods further comprise administering theselected anesthetic (e.g., a compound or mixture of compounds of FormulaI, Formula II, Formula III, Formula IV, Formula V, Formula VI, FormulaVII and/or Formula VIII, as described herein) to a patient. Theanesthetic can be administered by any route sufficient to achieve adesired anesthetic, amnestic, analgesic, or sedative effect. Forexample, the anesthetic can be administered intravenously,inhalationally, subcutaneously, intramuscularly, transdermally,topically, or by any other route to achieve an efficacious effect.

The anesthetic is administered at a dose sufficient to achieve a desiredanesthetic endpoint, for example, immobility, amnesia, analgesia,unconsciousness or autonomic quiescence.

Administered dosages for anesthetic agents are in accordance withdosages and scheduling regimens practiced by those of skill in the art.General guidance for appropriate dosages of pharmacological agents usedin the present methods is provided in Goodman and Gilman's ThePharmacological Basis of Therapeutics, 12th Edition, 2010, supra, and ina Physicians' Desk Reference (PDR), for example, in the 65^(th) (2011)or 66^(th) (2012) Eds., PDR Network, each of which is herebyincorporated herein by reference.

The appropriate dosage of anesthetic agents will vary according toseveral factors, including the chosen route of administration, theformulation of the composition, patient response, the severity of thecondition, the subject's weight, and the judgment of the prescribingphysician. The dosage can be increased or decreased over time, asrequired by an individual patient. Usually, a patient initially is givena low dose, which is then increased to an efficacious dosage tolerableto the patient.

Determination of an effective amount is well within the capability ofthose skilled in the art, especially in light of the detailed disclosureprovided herein. Generally, an efficacious or effective amount of acombination of one or more anesthetic agents is determined by firstadministering a low dose or small amount of the anesthetic, and thenincrementally increasing the administered dose or dosages, adding asecond or third medication as needed, until a desired effect is observedin the treated subject with minimal or no toxic side effects. Applicablemethods for determining an appropriate dose and dosing schedule foradministration of anesthetics are described, for example, in Goodman andGilman's The Pharmacological Basis of Therapeutics, 12th Edition, 2010,supra; in a Physicians' Desk Reference (PDR), supra; in Remington: TheScience and Practice of Pharmacy (Remington: The Science & Practice ofPharmacy), 21st Edition, 2011, Pharmaceutical Press, and Ansel'sPharmaceutical Dosage Forms and Drug Delivery Systems, Allen, et al.,eds., 9th Edition, 2010, Lippincott Williams & Wilkins; and inMartindale: The Complete Drug Reference, Sweetman, 2005, London:Pharmaceutical Press., and in Martindale, Martindale: The ExtraPharmacopoeia, 31st Edition, 1996, Amer Pharmaceutical Assn, each ofwhich are hereby incorporated herein by reference.

Dosage amount and interval can be adjusted individually to provideplasma levels of the active compounds which are sufficient to maintain adesired therapeutic effect. Preferably, therapeutically effective serumlevels will be achieved by administering a single dose, but efficaciousmultiple dose schedules are included in the invention. In cases of localadministration or selective uptake, the effective local concentration ofthe drug may not be related to plasma concentration. One having skill inthe art will be able to optimize therapeutically effective local dosageswithout undue experimentation.

The dosing of analog compounds can be based on the parent compound, atleast as a starting point.

In various embodiments, the compositions are delivered to the subjectvia a respiratory pathway, e.g., via inhalational, pulmonary and/orintranasal delivery. Technologies and devices for inhalationalanesthetic drug dosing are known in the art and described, e.g., inMILLER'S ANESTHESIA, Edited by Ronald D. Miller, et al., 2 vols, 7th ed,Philadelphia, Pa., Churchill Livingstone/Elsevier, 2010; and Meyer, etal., Handb Exp Pharmacol. (2008) (182):451-70. In one embodiment, thepharmaceutical compositions useful for inducing anesthesia can beadministered to deliver a dose of between about 0.1-10.0 percent of 1atmosphere (1 atm), e.g., 0.5-5.0 percent of 1 atm, e.g., about 1.0-3.5of 1 atm, e.g., about 0.1, 0.2, 0.3, 0.4. 0.5, 1.0, 1.5, 2.0, 2.5, 3.0,3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 or 10.0percent of 1 atm, e.g., delivered over the period of time of desiredanesthesia. The dose used will be dependent upon the drug potency, andthe compound or mixture of compounds administered.

Detailed information about the delivery of therapeutically active agentsin the form of vapors or gases is available in the art. The compoundwill typically be vaporized using a vaporizer using a carrier gas suchas oxygen, air, or helium, or a mixture thereof, to achieve a desireddrug concentration suitable for inhalation by use of a semi-open orsemi-closed anesthetic circuit, as is known to individuals familiar withthe art of anesthesia. The compound in a gaseous form may also bedirectly mixed with a carrier gas such as oxygen, air, or helium, or amixture thereof, to achieve a desired drug concentration suitable forinhalation by use of a semi-open or semi-closed anesthetic circuit, asis known to individuals familiar with the art of anesthesia. The drugmay also be administered by direct application of onto or through abreathing mask, also termed an open circuit, as is known to individualsfamiliar with the art of anesthesia. In animals, the drug may also beadministered into a closed chamber or container containing the animalsubject whereby the drug is delivered by the respiratory tract as theanimal breathes, as is known to individuals familiar with animalanesthesia.

In some aspects of the invention, the anesthetic compound or mixture ofcompounds, is dissolved or suspended in a suitable solvent, such aswater, ethanol, or saline, and administered by nebulization. A nebulizerproduces an aerosol of fine particles by breaking a fluid into finedroplets and dispersing them into a flowing stream of gas. Medicalnebulizers are designed to convert water or aqueous solutions orcolloidal suspensions to aerosols of fine, inhalable droplets that canenter the lungs of a patient during inhalation and deposit on thesurface of the respiratory airways. Typical pneumatic (compressed gas)medical nebulizers develop approximately 15 to 30 microliters of aerosolper liter of gas in finely divided droplets with volume or mass mediandiameters in the respirable range of 2 to 4 micrometers. Predominantly,water or saline solutions are used with low solute concentrations,typically ranging from 1.0 to 5.0 mg/mL.

Nebulizers for delivering an aerosolized solution to the lungs arecommercially available from a number of sources, including the AERx™(Aradigm Corp., Hayward, Calif.) and the Acorn II® (Vital Signs Inc.,Totowa, N.J.).

Metered dose inhalers are also known and available. Breath actuatedinhalers typically contain a pressurized propellant and provide ametered dose automatically when the patient's inspiratory effort eithermoves a mechanical lever or the detected flow rises above a presetthreshold, as detected by a hot wire anemometer. See, for example, U.S.Pat. Nos. 3,187,748; 3,565,070; 3,814,297; 3,826,413; 4,592,348;4,648,393; 4,803,978; and 4,896,832.

In some embodiments, the present invention provides methods forproducing analgesia in a subject, comprising administering to thesubject via the respiratory system an effective amount of a compound ora mixture of compounds which are described herein. In some embodiments,the analgesia includes tranquilization. In some embodiments, theanalgesia includes sedation. In some embodiments, the analgesia includesamnesia. In some embodiments, the analgesia includes a hypnotic state.In some embodiments, the analgesia includes a state of insensitivity tonoxious stimulation.

In some embodiments, the present invention provides methods of producingtranquilization or sedation in a subject, comprising administering tothe subject via the respiratory system an effective amount of a compoundor a mixture of compounds which are described herein. In certainembodiments, the present invention provides methods of producingtranquilization in a subject, comprising administering to the subjectvia the respiratory system an effective amount of a compound or amixture of compounds which are described herein. In some otherembodiments, the present invention provides methods of producing amnesiain a subject, comprising administering to the subject via therespiratory system an effective amount of a compound or a mixture ofcompounds which are described herein. Typically, the amount of acompound or a mixture of compounds which are described herein that isrequired to produce amnesia in a subject is larger than the amountrequired to produce tranquilization in a subject. In yet otherembodiments, the present invention provides methods of producing ahypnotic state in a subject, comprising administering to the subject viathe respiratory system an effective amount of a compound or a mixture ofcompounds which are described herein. Typically, the amount of acompound or a mixture of compounds which are described herein that isrequired to produce a hypnotic state in a subject is larger than theamount required to produce amnesia in a subject. In still otherembodiments, the present invention provides methods of producing a stateof insensitivity to noxious stimulation in a subject, comprisingadministering to the subject via the respiratory system an effectiveamount of a compound or a mixture of compounds which are describedherein. Typically, the amount of a compound or a mixture of compoundswhich are described herein that is required to produce a state ofinsensitivity to noxious stimulation in a subject is larger than theamount required to produce a hypnotic state in a subject.

In some embodiments, the present invention provides methods of inducingtranquilization or sedation in a subject, comprising administering tothe subject via the respiratory system an effective amount of a compoundor a mixture of compounds which are described herein. In certainembodiments, the present invention provides methods of inducingtranquilization in a subject, comprising administering to the subjectvia the respiratory system an effective amount of a compound or amixture of compounds which are described herein. In some otherembodiments, the present invention provides methods of inducing amnesiain a subject, comprising administering to the subject via therespiratory system an effective amount of a compound or a mixture ofcompounds which are described herein. Typically, the amount of acompound or a mixture of compounds which are described herein that isrequired to induce amnesia in a subject is larger than the amountrequired to induce tranquilization in a subject. In yet otherembodiments, the present invention provides methods of inducing ahypnotic state in a subject, comprising administering to the subject viathe respiratory system an effective amount of a compound or a mixture ofcompounds which are described herein. Typically, the amount of acompound or a mixture of compounds which are described herein that isrequired to induce a hypnotic state in a subject is larger than theamount required to induce amnesia in a subject. In still otherembodiments, the present invention provides methods of inducing a stateof insensitivity to noxious stimulation in a subject, comprisingadministering to the subject via the respiratory system an effectiveamount of a compound or a mixture of compounds which are describedherein. Typically, the amount of a compound or a mixture of compoundswhich are described herein that is required to induce a state ofinsensitivity to noxious stimulation in a subject is larger than theamount required to induce a hypnotic state in a subject.

The present invention includes methods of inducing a spectrum of statesof anesthesia in a subject as a function of the administered dosage of acompound or a mixture of compounds which are described herein. In someembodiments, the methods include administering low dosages of a compoundor a mixture of compounds which are described herein to inducetranquilization or sedation in a subject. In some other embodiments, themethods include administering higher dosages than that required toinduce tranquilization of a compound or a mixture of compounds which aredescribed herein to induce amnesia in a subject. In yet otherembodiments, the methods include administering even higher dosages thanthat required to induce amnesia in a subject of a compound or a mixtureof compounds which are described herein to induce a hypnotic state in asubject. In still other embodiments, the methods include administeringyet even higher dosages than that required to induce a hypnotic state ina subject of a compound or a mixture of compounds which are describedherein to induce a state of insensitivity to noxious stimulation in asubject.

V. Methods of Determining the Specificity of an Anesthetic for anAnesthetic Sensitive Receptor

The present invention provides methods for determining the specificityor selective activation of an anesthetic for an anesthetic-sensitivereceptor by determining the water solubility of the anesthetic andcomparing the water solubility of the anesthetic with a water solubilitycut-off or threshold value for the anesthetic-sensitive receptor. Ananesthetic with a water solubility that is below the water solubilitycut-off or threshold value for the anesthetic-sensitive receptor willnot activate that receptor. An anesthetic with a water solubility thatis above the water solubility cut-off or threshold value for theanesthetic-sensitive receptor can activate that receptor.

a. Anesthetics

The anesthetic can be any compound with anesthetic properties whenadministered to a patient. Generally, increasing doses of an anestheticcauses immobility, amnesia, analgesia, unconsciousness and autonomicquiescence in a patient. The anesthetics are general anesthetics (e.g.,systemic) and can be inhalational or injectable.

In some embodiments, the anesthetic is an inhalational anesthetic. Forexample, in some embodiments, the anesthetic is selected from the groupconsisting of ethers and halogenated ethers (including, e.g.,desflurane, enflurane, halothane, isoflurane, methoxyflurane,sevoflurane, diethyl ether, methyl propyl ether, and analogues thereof);alkanes and halogenated alkanes (including, e.g., halothane, chloroform,ethyl chloride, and analogues thereof), cycloalkanes andcyclohaloalkanes (including, e.g., cyclopropane and analogues thereof),alkenes and haloalkenes (including, e.g., trichloroethylene, ethylene,and analogues thereof), alkynes and haloalkynes and their analogues,vinyl ethers (including, e.g., ethyl vinyl ether, divinyl ether,fluoroxine, and analogues thereof). In some embodiments, the anestheticis selected from the group consisting of desflurane, enflurane,halothane, isoflurane, methoxyflurane, nitrous oxide, sevoflurane,xenon, and analogs thereof. In some embodiments, the anesthetic isselected from the group consisting of halogenated alcohols, halogenateddiethers, halogenated dioxanes, halogenated dioxolanes, halogenatedcyclopentanes, halogenated cyclohexanes, halogenated tetrahydrofuransand halogenated tetrahydropyrans, as described herein. In variousembodiments, the inhalational anesthetic is a compound or mixture ofcompounds of Formula I, Formula II, Formula III, Formula IV, Formula V,Formula VI, Formula VII and/or Formula VIII, as described herein.

In some embodiments, the anesthetic is an injectable anesthetic orsedative drug. For example, in some embodiments, the anesthetic isselected from the group consisting of alkyl phenols (including, e.g.,propofol and analogues thereof), imidazole derivatives (including, e.g.,etomidate, metomidate, clonidine, detomidine, medetomidine,dexmedetomidine, and analogues thereof), barbiturates and analoguesthereof, benzodiazepines and analogues thereof, cyclohexylamines(including, e.g., ketamine, tiletamine, and analogues thereof), steroidanesthetics (including, e.g., alphaxalone and analogues thereof),opioids and opioid-like compounds (including, e.g., natural morphine andderivatives, codeine and derivatives, papaverine and derivatives,thebaine and derivatives, morphinans and derivatives,diphenylpropylamines and derivatives, benzmorphans and derivatives,phenylpiperadines and derivatives), phenothiazines and halogenatedphenothiazine comopounds and analogues thereof, buterophenones andhalogenated buterophenone compounds and analogues thereof, guaicols andhalogenated guaicols (including, e.g., eugenol and analogues thereof),and substituted benzoates and halobenzoate derivatives (including, e.g.,tricaine and analogues thereof). In some embodiments, the anesthetic isselected from the group consisting of propofol, etomidate, barbiturates,benzodiazepines, ketamine, and analogs thereof.

Anesthetic compounds are generally known in the art and are describedin, e.g., Goodman and Gilman's The Pharmacological Basis ofTherapeutics, 12th Edition, 2010, supra, and in a Physicians' DeskReference (PDR), for example, in the 65^(th) (2011) or 66^(th) (2012)Eds., PDR Network.

b. Anesthetic-Sensitive Receptors

Anesthetic-sensitive receptors are receptors and ion channels that bindto and are activated by anesthetics. Anesthetic-sensitive receptorsinclude 2-, 3-, 4-, and 7-transmembrane receptor proteins. Exemplaryanesthetic-sensitive receptors include glycine receptors, GABAreceptors, two-pore domain potassium channels (K_(2P)), voltage-gatedsodium channels (Na_(v)), NMDA receptors, opioid receptors and subtypesof such receptors. Anesthetic-sensitive receptors are well-known in theart. Their sequences are well characterized.

N-methyl-D-aspartate (NMDA) receptor channels are heteromers composed ofthree different subunits: NR1 (GRIN1), NR2 (GRIN2A, GRIN2B, GRIN2C, orGRIN2D) and NR3 (GRIN3A or GRIN3B). The NR2 subunit acts as the agonistbinding site for glutamate. This receptor is the predominant excitatoryneurotransmitter receptor in the mammalian brain. NMDA receptors arereviewed, e.g., in Albensi, Curr Pharm Des (2007) 13(31):3185-94:Paoletti and Neyton, Curr Opin Pharmacol (2007) 7(1):39-47; Cull-Candy,et al., Curr Opin Neurobiol (2001) 11(3):327-35. The GenBank AccessionNos. for isoforms of human NMDA NR1 (NMDAR1, GRIN1) includeNM_000832.6→NP_000823.4 (NR1-1), NM_021569.3→NP_067544.1 (NR1-2),NM_007327.3→NP_015566.1 (NR1-3), NM_001185090.1→NP_001172019.1 (NR1-4);NM_001185091.1→NP_001172020.1 (NR1-5); the GenBank Accession Nos. forisoforms of human NMDA NR2A (NMDAR2A, GRIN2A) includeNM_000833.3→NP_000824.1 (isoform 1), NM_001134407.1→NP_001127879.1(isoform 1), NM_001134408.1→NP_001127880.1 (isoform 2); the GenBankAccession No. for human NMDA NR2B (NMDAR2B, GRIN2B) includesNM_000834.3→NP_000825.2; the GenBank Accession No. for human NMDA NR2C(NMDAR2C, GRIN2C) includes NM_000835.3→NP_000826.2; the GenBankAccession No. for human NMDA NR2D (NMDAR2D, GRIN2D) includesNM_000836.2→NP_000827.2; the GenBank Accession No. for human NMDA NR3A(NMDAR3A, GRIN3A) includes NM_133445.2→NP_597702.2; the GenBankAccession No. for human NMDA NR3B (NMDAR3B, GRIN3B) includesNM_138690.1→NP_619635.1. NMDA receptor sequences are alsowell-characterized for non-human mammals.

Gamma-aminobutyric acid (GABA)-A receptors are pentameric, consisting ofproteins from several subunit classes: alpha, beta, gamma, delta andrho. GABA receptors are reviewed, e.g., in Belelli, et al., J Neurosci(2009) 29(41):12757-63; and Munro, et al., Trends Pharmacol Sci (2009)30(9):453-9. GenBank Accession Nos. for variants of human GABA-Areceptor, alpha 1 (GABRA1) include NM_000806.5→NP_000797.2 (variant 1),NM_001127643.1→NP_001121115.1 (variant 2), NM_001127644.1→NP_001121116.1(variant 3), NM_001127645.1→NP_001121117.1 (variant 4),NM_001127646.1→NP_001121118.1 (variant 5), NM_001127647.1→NP_001121119.1(variant 6), NM_001127648.1→NP_001121120.1 (variant 7). GenBankAccession Nos. for variants of human GABA-A receptor, alpha 2 (GABRA2)include NM_000807.2→NP_000798.2 (variant 1),NM_001114175.1→NP_001107647.1 (variant 2). GenBank Accession No. forhuman GABA-A receptor, alpha 3 (GABRA3) includesNM_000808.3→NP_000799.1. GenBank Accession Nos. for variants of humanGABA-A receptor, alpha 4 (GABRA4) include NM_000809.3→NP_000800.2(variant 1), NM_001204266.1→NP_001191195.1 (variant 2),NM_001204267.1→NP_001191196.1 (variant 3). GenBank Accession Nos. forvariants of human GABA-A receptor, alpha 5 (GABRA5) includeNM_000810.3→NP_000801.1 (variant 1), NM_001165037.1→NP_001158509.1(variant 2). GenBank Accession No. for human GABA-A receptor, alpha 6(GABRA6) includes NM_000811.2→NP_000802.2. GenBank Accession No. forhuman GABA-A receptor, beta 1 (GABRB1) includes NM_000812.3→NP_000803.2.GenBank Accession Nos. for variants of human GABA-A receptor, beta 2(GABRB2) include NM_021911.2→NP_068711.1 (variant 1),NM_000813.2→NP_000804.1 (variant 2). GenBank Accession Nos. for variantsof human GABA-A receptor, beta 3 (GABRB3) include NM_000814.5NP_000805.1 (variant 1), NM_021912.4→NP_068712.1 (variant 2),NM_001191320.1→NP_001178249.1 (variant 3), NM_001191321.1→NP_001178250.1(variant 4). GenBank Accession No. for human GABA-A receptor, gamma 1(GABRG1) includes NM_173536.3→NP_775807.2. GenBank Accession Nos. forvariants of human GABA-A receptor, gamma 2 (GABRG2) includeNM_198904.2→NP_944494.1 (variant 1), NM_000816.3→NP_000807.2 (variant2), NM_198903.2→NP_944493.2 (variant 3). GenBank Accession No. for humanGABA-A receptor, gamma 3 (GABRG3) includes NM_033223.4→NP_150092.2.GenBank Accession Nos. for variants of human GABA-A receptor, rho 1(GABRR1) include NM_002042.4→NP_002033.2 (variant 1),NM_001256703.1→NP_001243632.1 (variant 2), NM_001256704.1→NP_001243633.1(variant 3), NM_001267582.1→NP_001254511.1 (variant 4). GenBankAccession No. for human GABA-A receptor, rho 2 (GABRR2) includesNM_002043.2→NP_002034.2. GenBank Accession No. for human GABA-Areceptor, rho 3 (GABRR3) includes NM_001105580.2→NP_001099050.1.

Voltage-sensitive sodium channels are heteromeric complexes consistingof a large central pore-forming glycosylated alpha subunit, and twosmaller auxiliary beta subunits. Voltage-gated sodium channels arereviewed, e.g., in French and Zamponi, IEEE Trans Nanobioscience (2005)4(1):58-69; Bezanilla, IEEE Trans Nanobioscience (2005) 4(1):34-48;Doherty and Farmer, Handb Exp Pharmacol (2009) 194:519-61; England,Expert Opin Investig Drugs (2008) 17(12):1849-64; and Marban, et al., JPhysiol (1998) 508(3):647-57. GenBank Accession Nos. for variants ofsodium channel, voltage-gated, type I, alpha subunit (SCN1A, Nav1.1)include NM_001165963.1→NP_001159435.1 (variant 1),NM_006920.4→NP_008851.3 (variant 2), NM_001165964.1→NP_001159436.1(variant 3), NM_001202435.1→NP_001189364.1 (variant 4). GenBankAccession Nos. for variants of sodium channel, voltage-gated, type II,alpha subunit (SCN2A, Nav1.2) include NM_021007.2→NP_066287.2 (variant1), NM_001040142.1→NP_001035232.1 (variant 2),NM_001040143.1→NP_001035233.1 (variant 3). GenBank Accession Nos. forvariants of sodium channel, voltage-gated, type III, alpha subunit(SCN3A, Nav1.3) include NM_006922.3→NP_008853.3 (variant 1),NM_001081676.1→NP_001075145.1 (variant 2), NM_001081677.1→NP_001075146.1(variant 3). GenBank Accession No. for sodium channel, voltage-gated,type IV, alpha subunit (SCN4A, Nav1.4) includes NM_000334.4→NP_000325.4.GenBank Accession Nos. for variants of sodium channel, voltage-gated,type V, alpha subunit (SCN5A, Nav1.5) include NM_198056.2→NP_932173.1(variant 1), NM_000335.4→NP_000326.2 (variant 2),NM_001099404.1→NP_001092874.1 (variant 3), NM_001099405.1→NP_001092875.1(variant 4), NM_001160160.1→NP_001153632.1 (variant 5),NM_001160161.1→NP_001153633.1 (variant 6). GenBank Accession No. forsodium channel, voltage-gated, type VII, alpha subunit (SCN6A, SCN7A,Nav2.1, Nav2.2) includes NM_002976.3→NP_002967.2. GenBank Accession Nos.for variants of sodium channel, voltage-gated, type VIII, alpha subunit(SCN8A, Nav1.6) include NM_014191.3→NP_055006.1 (variant 1),NM_001177984.2→NP_001171455.1 (variant 2). GenBank Accession No. forsodium channel, voltage-gated, type IX, alpha subunit (SCN9A, Nav1.7)includes NM_002977.3→NP_002968.1. GenBank Accession No. for sodiumchannel, voltage-gated, type X, alpha subunit (SCN10A, Nav1.8) includesNM_006514.2→NP_006505.2. GenBank Accession No. for sodium channel,voltage-gated, type XI, alpha subunit (SCN11A, Nav1.9) includesNM_014139.2→NP_054858.2. GenBank Accession Nos. for variants of sodiumchannel, voltage-gated, type I, beta subunit (SCN1B) includeNM_001037.4→NP_001028.1 (variant a), NM_199037.3→NP_950238.1 (variantb). GenBank Accession No. for sodium channel, voltage-gated, type II,beta subunit (SCN2B) includes NM_004588.4→NP_004579.1. GenBank AccessionNos. for variants of sodium channel, voltage-gated, type III, betasubunit (SCN3B) include NM_018400.3→NP_060870.1 (variant 1),NM_001040151.1→NP_001035241.1 (variant 2). GenBank Accession Nos. forvariants of sodium channel, voltage-gated, type IV, beta subunit (SCN4B)include NM_174934.3→NP_777594.1 (variant 1),NM_001142348.1→NP_001135820.1 (variant 2), NM_001142349.1→NP_001135821.1(variant 3).

Glycine receptors are pentamers composed of alpha and beta subunits.Glycine receptors are reviewed, e.g., in Kuhse, et al., Curr OpinNeurobiol (1995) 5(3):318-23; Betz, et al., Ann NY Acad Sci (1999)868:667-76; Colquhoun and Sivilotti, Trends Neurosci (2004)27(6):337-44; and Cascio, J Biol Chem (2004) 279(19):19383-6. GenBankAccession Nos. for variants of glycine receptor, alpha 1 (GLRA1) includeNM_001146040.1→NP_001139512.1 (variant 1), NM_000171.3→NP_000162.2(variant 2). GenBank Accession Nos. for variants of glycine receptor,alpha 2 (GLRA2) include NM_002063.3→NP_002054.1 (variant 1),NM_001118885.1→NP_001112357.1 (variant 2), NM_001118886.1→NP_001112358.1(variant 3) NM_001171942.1→NP_001165413.1 (variant 4). GenBank AccessionNos. for variants of glycine receptor, alpha 3 (GLRA3) includeNM_006529.2→NP_006520.2 (isoform a), NM_001042543.1→NP_001036008.1(isoform b). GenBank Accession Nos. for variants of glycine receptor,alpha 4 (GLRA4) include NM_001024452.2→NP_001019623.2 (variant 1),NM_001172285.1→NP_001165756.1 (variant 2). GenBank Accession Nos. forvariants of glycine receptor, beta (GLRB) includeNM_000824.4→NP_000815.1 (variant 1), NM_001166060.1→NP_001159532.1(variant 2), NM_001166061.1→NP_001159533.1 (variant 3).

Two-pore potassium channels are reviewed, e.g., in Besana, et al.,Prostaglandins Other Lipid Mediat (2005) 77(1-4):103-10; Lesage andLazdunski, Am J Physiol Renal Physiol (2000) 279(5):F793-801; Baylissand Barrett, Trends Pharmacol Sci (2008) 29(11):566-75; Reyes, et al., JBiol Chem (1998) 273(47):30863-9; and Kang and Kim, Am J Physiol CellPhysiol (2006) 291(1):C138-46. GenBank Accession Nos. for variants ofpotassium channel, subfamily K, member 2 (KCNK2, TREK1, K2p2.1) includeNM_001017424.2→NP_001017424.1 (variant 1), NM_014217.3→NP_055032.1(variant 2), NM_001017425.2→NP_001017425.2 (variant 3). GenBankAccession No. for potassium channel, subfamily K, member 3 (KCNK3, TASK;TBAK1; K2p3.1) includes NM_002246.2→NP_002237.1. GenBank Accession No.for potassium channel, subfamily K, member 6 (KCNK6, KCNK8; TWIK2;K2p6.1) includes 1.NM_004823.1→NP_004814.1.

c. Determining Water Solubility of the Anesthetic

The water solubility of the anesthetic can be determined using anymethod known in the art. For example, the water solubility can bedetermined using a computer implemented algorithm. One such algorithm isavailable through SciFinder Scholar provided by the American ChemicalSociety and available on the worldwide web at scifinder.cas.org. Watersolubility values using SciFinder Scholar are calculated using AdvancedChemistry Development (ACD/Labs) Software V9.04 for Solaris (1994-2009ACD/Labs). Solubility values are calculated at pH=7 in pure water at 25°C. Other computer-implemented algorithms for determining the watersolubility of an anesthetic find use and are known in the art. Forexample, software for calculating water solubility is also commerciallyavailable from Advanced Chemistry Development of Toronto, Ontario,Canada (on the worldwide web at acdlabs.com). Chemix software isavailable without charge and can be downloaded from the internet athome.c2i.net/astandne.

Alternatively, the water solubility of a compound can be empiricallydetermined. For example, the conditions in which anesthetic effects aremeasured in a biological system are usually at pH (7.4), in a bufferedelectrolyte solution at 22-23° C. These differences likely account forthe small variation in the NMDA solubility cutoff for differenthydrocarbon groups shown in FIG. 4.

d. Determining the Specificity of the Anesthetic for theAnesthetic-Sensitive Receptor

The water solubility of the anesthetic is compared with the solubilitycut-off or threshold concentration of an anesthetic-sensitive receptor.If the molar water solubility of the anesthetic is less than thesolubility cut-off or threshold concentration of an anesthetic-sensitivereceptor, then the anesthetic will not activate thatanesthetic-sensitive receptor. If the water solubility of the anestheticis greater than the solubility cut-off or threshold concentration of ananesthetic-sensitive receptor, then the anesthetic can activate thatanesthetic-sensitive receptor.

For example, in some embodiments, an anesthetic with a molar watersolubility below a predetermined solubility threshold concentration forNa_(v) channels does not inhibit Na_(v) channels, but can inhibit NMDAreceptors, potentiate two-pore domain potassium channels (K_(2P)),potentiate glycine receptors and potentiate GABA_(A) receptors.

In some embodiments, an anesthetic with a molar water solubility below apredetermined solubility threshold concentration for NMDA receptors doesnot inhibit Na_(v) channels or inhibit NMDA receptors, but canpotentiate two-pore domain potassium channels (K_(2P)), potentiateglycine receptors and potentiate GABA_(A) receptors.

In some embodiments, an anesthetic with a molar water solubility below apredetermined solubility threshold concentration for two-pore domainpotassium channels (K_(2P)) does not inhibit Na_(v) channels, inhibitNMDA receptors or potentiate two-pore domain potassium channel (K_(2P))currents, but can potentiate glycine receptors and potentiate GABA_(A)receptors.

In some embodiments, an anesthetic with a molar water solubility below apredetermined solubility threshold concentration for GABA_(A) receptorsdoes not inhibit Na_(v) channels, inhibit NMDA receptors, potentiatetwo-pore domain potassium channel (K_(2P)) currents, or potentiateGABA_(A) receptors but can potentiate glycine receptors.

In some embodiments, the anesthetic has a molar water solubility below apredetermined solubility threshold concentration for NMDA receptors(e.g., below about 1.1 mM) and potentiates GABA_(A) receptors but doesnot inhibit NMDA receptors. In some embodiments, the anesthetic has awater solubility greater than a predetermined solubility thresholdconcentration for NMDA receptors (e.g., greater than about 1.1 mM) andboth potentiates GABA_(A) receptors and inhibits NMDA receptors.

In various embodiments, the solubility threshold concentration for NMDAreceptors is in the range of between about 0.45 mM and about 2.8 mM, forexample between about 1 mM and about 2 mM, for example, about, 0.1 mM,0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM,1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mMor 2.0 mM. In some embodiments, the predetermined solubility thresholdconcentration for NMDA receptors is about 1.1 mM. In some embodiments,the predetermined solubility threshold concentration for NMDA receptorsis about 2 mM. In some embodiments, the anesthetic has a molar watersolubility that is below the threshold water solubility cut-offconcentration of an NMDA receptor, and therefore does not inhibit theNMDA receptor. In some embodiments, the anesthetic has a watersolubility that is below about 2 mM, for example, below about 2.0 mM,1.9 mM, 1.8 mM, 1.7 mM, 1.6 mM, 1.5 mM, 1.4 mM, 1.3 mM, 1.2 mM, 1.1 mMor 1.0 mM. In some embodiments, the anesthetic has a water solubilitythat is above the threshold water solubility cut-off concentration of anNMDA receptor, and therefore can inhibit the NMDA receptor. In someembodiments, the anesthetic has a molar water solubility that is aboveabout 1.0 mM, for example, above about 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM,1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM or 2.0 mM.

In various embodiments, the solubility threshold concentration fortwo-pore domain potassium channels (K_(2P)) receptors is in the range ofabout 0.10-1.0 mM, for example, about 0.10 mM, 0.20 mM, 0.26 mM, 0.30mM, 0.35 mM, 0.40 mM, 0.45 mM, 0.50 mM, 0.55 mM, 0.60 mM, 0.65 mM, 0.70mM, 0.75 mM, 0.80 mM, 0.85 mM, 0.90 mM, 0.95 mM or 1.0 mM. In someembodiments, the predetermined solubility threshold concentration fortwo-pore domain potassium channels (K_(2P)) receptors is about 0.26 mM.In some embodiments, two-pore domain potassium channels (K_(2P))receptor is a TREK or a TRESK receptor. In some embodiments, theanesthetic has a molar water solubility that is below the thresholdwater solubility cut-off concentration of a two-pore domain potassiumchannels (K_(2P)) receptor (e.g., below about 0.26 mM), and thereforedoes not potentiate the two-pore domain potassium channels (K_(2P))receptor. In some embodiments, the anesthetic has a molar watersolubility that is above the threshold water solubility cut-offconcentration of a two-pore domain potassium channels (K_(2P)) receptor(e.g., above about 0.26 mM), and therefore can potentiate the two-poredomain potassium channels (K_(2P)) receptor.

In various embodiments, the solubility threshold concentration forvoltage-gated sodium channels (Na_(v)) is in the range of about 1.2 toabout 1.9 mM, for example, about 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM,1.7 mM, 1.8 mM or 1.9 mM. In some embodiments, the predeterminedsolubility threshold concentration for voltage-gated sodium channels(Na_(v)) is about 1.2 mM. In some embodiments, the predeterminedsolubility threshold concentration for voltage-gated sodium channels(Na_(v)) is about 1.9 mM. In some embodiments, the anesthetic has amolar water solubility that is below the threshold water solubilitycut-off concentration of a voltage-gated sodium channel (Na_(v)) (e.g.,below about 1.2 mM), and therefore does not inhibit the voltage-gatedsodium channel (Na_(v)). In some embodiments, the anesthetic has a watersolubility that is above the threshold water solubility cut-offconcentration of a voltage-gated sodium channel (Na_(v)) (e.g., aboveabout 1.9 mM) and therefore can inhibit the voltage-gated sodium channel(Na_(v)).

In various embodiments, the solubility threshold concentration forGABA_(A) receptors is in the range of about 50-100 μM, for example,about 50 μM, 60 μM, 65 μM, 68 μM, 70 μM, 75 μM, 80 μM, 85 μM, 90 μM, 95μM or 100 μM. In some embodiments, the predetermined solubilitythreshold concentration for GABA_(A) receptors is about 68 μM. In someembodiments, the anesthetic has a molar water solubility that is belowthe threshold water solubility cut-off concentration of a GABA_(A)receptor (e.g., below about 68 μM), and therefore does not potentiatethe GABA_(A) receptor. In some embodiments, the anesthetic has a watersolubility that is above the threshold water solubility cut-offconcentration of a GABA_(A) receptor (e.g., above about 68 μM), andtherefore can potentiate the GABA_(A) receptor.

In various embodiments, the solubility threshold concentration forglycine receptors is in the range of about 0.7-to-89 μM, for example,about 0.7 μM, 3.9 μM, 7.8 μM, 17 μM, 31 μM, 62 μM, 89 μM. In someembodiments, the predetermined solubility threshold concentration forglycine receptors is about 7.8 μM. In some embodiments, the anesthetichas a molar water solubility that is below the threshold watersolubility cut-off concentration of a glycine receptor, and thereforedoes not activate the glycine receptor. In some embodiments, theanesthetic has a water solubility that is above the threshold watersolubility cut-off concentration of a glycine receptor.

e. Selecting the Desired Anesthetic

In some embodiments, the methods further comprise the step of selectingan appropriate or desired anesthetic, e.g., based on the subset ofanesthetic-sensitive receptors that can be activated by the anesthetic.

For example, the selected anesthetic can have a water solubility below apredetermined solubility threshold concentration for Na_(v) channels(e.g., below about 1.2 mM), such that the anesthetic does not inhibitNa_(v) channels, but can inhibit NMDA receptors, potentiate two-poredomain potassium channels (K_(2P)), potentiate glycine receptors andpotentiate GABA_(A) receptors.

In some embodiments, the selected anesthetic can have a water solubilitybelow a predetermined solubility threshold concentration for NMDAreceptors (e.g., below about 1.1 mM) such that the anesthetic does notinhibit Na_(v) channels or inhibit NMDA receptors, but can potentiatetwo-pore domain potassium channels (K_(2P)), potentiate glycinereceptors and potentiate GABA_(A) receptors.

In some embodiments, the selected anesthetic can have a water solubilitybelow a predetermined solubility threshold concentration for two-poredomain potassium channels (K_(2P)) (e.g., below about 0.26 mM) such thatthe anesthetic does not inhibit Na_(v) channels, inhibit NMDA receptorsor potentiate two-pore domain potassium channel (K_(2P)) currents, butcan potentiate glycine receptors and potentiate GABA_(A) receptors.

In some embodiments, the selected anesthetic can have a water solubilitybelow a predetermined solubility threshold concentration for GABA_(A)receptors (e.g., below about 68 μM) such that the anesthetic does notinhibit Na_(v) channels, inhibit NMDA receptors, potentiate two-poredomain potassium channel (K_(2P)) currents, or potentiate GABA_(A)receptors but can potentiate glycine receptors.

In some embodiments, the selected anesthetic can have a water solubilitybelow a predetermined solubility threshold concentration for NMDAreceptors (e.g., below about 1.1 mM) such that the anestheticpotentiates GABA_(A) receptors but does not inhibit NMDA receptors. Insome embodiments, the anesthetic has a water solubility greater than apredetermined solubility threshold concentration for NMDA receptors(e.g., greater than about 1.1 mM) and both potentiates GABA_(A)receptors and inhibits NMDA receptors.

In some embodiments, the selected anesthetic has a water solubility suchthat the anesthetic does not activate NMDA receptors, two-pore domainpotassium channels (K2P), voltage-gated sodium channels (Nav), orGABA_(A) receptors, but can activate glycine receptors. The anestheticmay have a water solubility that is less than about 7.8 μM.

The selected anesthetics usually have a water solubility that is greaterthan 7.8 μM.

VI. Methods of Modulating the Specificity of an Anesthetic for anAnesthetic-Sensitive Receptor by Altering the Water Solubility of theAnesthetic

The invention also provides methods for modulating (i.e., increasing ordecreasing) the specificity of an anesthetic for an anesthetic-sensitivereceptor or a subset of anesthetic-sensitive receptors by adjusting thewater solubility of the anesthetic. The anesthetic can be chemicallymodified or altered to increase or decrease the water solubility andhence the specificity of the anesthetic for the anesthetic-sensitivereceptor or the subset of anesthetic-sensitive receptors.

In various embodiments, this method can be performed by determining thewater solubility of the parent anesthetic and then comparing the watersolubility of the parent anesthetic threshold cut-off value of ananesthetic-sensitive receptor, as described above. If the watersolubility of the anesthetic is below the water solubility thresholdcut-off concentration of the anesthetic-sensitive receptor, then theanesthetic will not modulate the receptor. If the capacity to modulatethe anesthetic-sensitive receptor is desired, the water solubility ofthe anesthetic can be sufficiently increased, e.g., by chemicallymodifying the parent anesthetic, such that the analog of the parentanesthetic has a water solubility above the water solubility thresholdcut-off concentration of the receptor or the subset of receptors ofinterest. In this case, the analog of the parent anesthetic can modulatethe anesthetic-sensitive receptor or a subset of anesthetic-sensitivereceptors of interest.

Conversely, if the water solubility of the anesthetic is above the watersolubility threshold cut-off concentration of the anesthetic-sensitivereceptor, then the anesthetic can modulate the receptor. If the capacityto modulate the anesthetic-sensitive receptor is not desired, then thewater solubility of the anesthetic can be sufficiently decreased, e.g.,by chemically modifying the parent anesthetic, such that the analog ofthe parent anesthetic has a water solubility below the water solubilitythreshold cut-off concentration of the anesthetic-sensitive receptor orthe subset of receptors of interest. In this case, the analog of theparent anesthetic does not modulate the receptors or subset of receptorsof interest.

The water solubility of the parent anesthetic can be adjusted usingmethods well known in the art. For example, the parent anesthetic can bechemically modified. Substituents on the parent anesthetic can be added,removed or changed, to increase or decrease the water solubility of thecompound, as desired. The resulting analogs of the parent anestheticeither gain or lose the functional ability to activate theanesthetic-sensitive receptor, as desired, and have an increased ordecreased water solubility, respectively, in comparison to the parentanesthetic. The anesthetic analogs of use retain the functional abilityto effect anesthesia. The potency and/or efficacy of the anestheticanalogs, however, may be increased or decreased in comparison to theparent anesthetic.

For example, to decrease the water solubility of the anesthetic, polaror heteroatom substituents, e.g., hydroxyl or amino groups, can beremoved or substituted with more hydrophobic substituents, e.g., ahalogen or an alkyl group. Water solubility can also be decreased, e.g.,by increasing the number of carbons on alkyl substituents, e.g., alkane,alkene, alkyne, alkoxy, etc. One, two, three, four, or more carbons canbe added to the alkyl substituent, as needed, to decrease the watersolubility of the anesthetic, as desired.

Conversely, to increase the water solubility of the anesthetic,hydrophobic substituents, e.g., a halogen or an alkyl group, can beremoved or substituted with polar or heteroatom substituents, e.g.,hydroxyl or amino groups. Water solubility can also be increased, e.g.,by decreasing the number of carbons on alkyl substituents, e.g., alkane,alkene, alkyne, alkoxy, etc. One, two, three, four, or more carbons canbe removed from the alkyl substituent, as needed, to increase the watersolubility of the anesthetic, as desired.

For example, in some embodiments, the anesthetic is adjusted to have awater solubility below a predetermined solubility thresholdconcentration for NMDA receptors (e.g., below about 1.1 mM) such thatthe anesthetic does not inhibit Na_(v) channels or inhibit NMDAreceptors, but can potentiate two-pore domain potassium channels(K_(2P)), potentiate glycine receptors and potentiate GABA_(A)receptors. The water solubility threshold concentrations for thedifferent anesthetic-sensitive receptors are as described above andherein.

In some embodiments, the anesthetic is adjusted to have a watersolubility below a predetermined solubility threshold concentration fortwo-pore domain potassium channels (K_(2P)) (e.g., below about 0.26 mM)such that the anesthetic does not inhibit Nay channels, inhibit NMDAreceptors or potentiate two-pore domain potassium channel (K_(2P))currents, but can potentiate glycine receptors and potentiate GABA_(A)receptors.

In some embodiments, the anesthetic is adjusted to have a watersolubility below a predetermined solubility threshold concentration forvoltage-gated sodium channels (Na_(v)) (e.g., below about 1.2 mM) suchthat the anesthetic does not inhibit Nay channels, but can inhibit NMDAreceptors, potentiate two-pore domain potassium channels (K_(2P)),potentiate glycine receptors and potentiate GABA_(A) receptors.

In some embodiments, the anesthetic is adjusted to have a watersolubility above a predetermined solubility threshold concentration forNMDA receptors (e.g., above about 1.1 mM) such that the anesthetic canboth potentiate GABA_(A) receptors and inhibit NMDA receptors.

In various embodiments, the anesthetic is adjusted to have a watersolubility that is below the threshold water solubility cut-offconcentration of an NMDA receptor, and therefore does not activate theNMDA receptor. In some embodiments, an anesthetic is adjusted to have awater solubility that is below about 2 mM, for example, below about 2.0mM, 1.9 mM, 1.8 mM, 1.7 mM, 1.6 mM, 1.5 mM, 1.4 mM, 1.3 mM, 1.2 mM, 1.1mM or 1.0 mM. In some embodiments, an anesthetic is adjusted to have awater solubility that is below about 1.1 mM. In some embodiments, theanesthetic is adjusted to have a water solubility that is above thethreshold water solubility cut-off concentration of an NMDA receptor. Insome embodiments, an anesthetic is adjusted to have a water solubilitythat is above about 1.0 mM, for example, above about 1.1 mM, 1.2 mM, 1.3mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM or 2.0 mM. In someembodiments, an anesthetic is adjusted to have a water solubility thatis above about 1.1 mM.

In some embodiments, the anesthetic is adjusted to have a watersolubility that is below the threshold water solubility cut-offconcentration of a two-pore domain potassium channels (K_(2P)) receptor,and therefore does not potentiate the two-pore domain potassium channels(K_(2P)) receptor. In some embodiments, the anesthetic is adjusted tohave a water solubility that is below about 0.10 mM, 0.20 mM, 0.26 mM,0.30 mM, 0.35 mM, 0.40 mM, 0.45 mM, 0.50 mM, 0.55 mM, 0.60 mM, 0.65 mM,0.70 mM, 0.75 mM, 0.80 mM, 0.85 mM, 0.90 mM, 0.95 mM or 1.0 mM. In someembodiments, the anesthetic is adjusted to have a water solubility thatis below about 0.26 mM. In some embodiments, the anesthetic is adjustedto have a water solubility that is above the threshold water solubilitycut-off concentration of a two-pore domain potassium channels (K_(2P))receptor, and therefore can potentiate the two-pore domain potassiumchannels (K_(2P)) receptor. In some embodiments, the anesthetic isadjusted to have a water solubility that is above about 0.10 mM, 0.20mM, 0.26 mM, 0.30 mM, 0.35 mM, 0.40 mM, 0.45 mM, 0.50 mM, 0.55 mM, 0.60mM, 0.65 mM, 0.70 mM, 0.75 mM, 0.80 mM, 0.85 mM, 0.90 mM, 0.95 mM or 1.0mM. In some embodiments, the anesthetic is adjusted to have a watersolubility that is above about 0.26 mM. In some embodiments, two-poredomain potassium channels (K_(2P)) receptor is a TREK or a TRESKreceptor.

In some embodiments, the anesthetic is adjusted to have a watersolubility that is below the threshold water solubility cut-offconcentration of a voltage-gated sodium channel (Na_(v)), and thereforedoes not inhibit the voltage-gated sodium channel (Na_(v)). In someembodiments, the anesthetic is adjusted to have a water solubility thatis below about 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM or1.9 mM. In some embodiments, the anesthetic is adjusted to have a watersolubility that is below about 1.2 mM. In some embodiments, theanesthetic is adjusted to have a water solubility that is above thethreshold water solubility cut-off concentration of a voltage-gatedsodium channel (Na_(v)), and therefore can inhibit the voltage-gatedsodium channel (Na_(v)). In some embodiments, the anesthetic is adjustedto have a water solubility that is above about 1.2 mM, 1.3 mM, 1.4 mM,1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM or 1.9 mM. In some embodiments, theanesthetic is adjusted to have a water solubility that is above about1.9 mM.

In some embodiments, the anesthetic is adjusted to have a watersolubility that is below the threshold water solubility cut-offconcentration of a GABA_(A) receptor, and therefore does not potentiatethe GABA_(A) receptor. In some embodiments, the anesthetic is adjustedto have a water solubility that is below about 50 μM, 60 μM, 65 μM, 68μM, 70 μM, 75 μM, 80 μM, 85 μM, 90 μM, 95 μM or 100 μM. In someembodiments, the anesthetic is adjusted to have a water solubility thatis below about 68 μM. In some embodiments, the anesthetic is adjusted tohave a water solubility that is above the threshold water solubilitycut-off concentration of a GABA_(A) receptor, and therefore canpotentiate the GABA_(A) receptor. In some embodiments, the anesthetic isadjusted to have a water solubility that is above about 50 μM, 60 μM, 65μM, 68 μM, 70 μM, 75 μM, 80 μM, 85 μM, 90 μM, 95 μM or 100 μM. In someembodiments, the anesthetic is adjusted to have a water solubility thatis above about 68 μM.

In some embodiments, the anesthetic is adjusted to have a watersolubility that is below the threshold water solubility cut-offconcentration of a glycine receptor, and therefore does not potentiatethe glycine receptor. In some embodiments, the anesthetic is adjusted tohave a water solubility that is above the threshold water solubilitycut-off concentration of a glycine receptor, and therefore canpotentiate the glycine receptor. The solubility cut-off for the glycinereceptor is about 7.8 μM, but may range between 0.7 and 89 μM.

In some embodiments, the methods further comprise the step of selectingthe anesthetic analog with the desired water solubility. In someembodiments, the methods further comprise the step of administering theanesthetic analog, as described above and herein.

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed invention.

Example 1

Hydrocarbon Molar Water Solubility Predicts NMDA vs. GABA_(A) ReceptorModulation

Background: Many anesthetics modulate 3-transmembrane (such as NMDA) and4-transmembrane (such as GABA_(A)) receptors. Clinical and experimentalanesthetics exhibiting receptor family specificity often have low watersolubility. We determined that the molar water solubility of ahydrocarbon could be used to predict receptor modulation in vitro.

Methods: GABA_(A) (α₁β₂γ_(2s)) or NMDA (NR1/NR2A) receptors wereexpressed in oocytes and studied using standard two-electrode voltageclamp techniques. Hydrocarbons from 14 different organic functionalgroups were studied at saturated concentrations, and compounds withineach group differed only by the carbon number at the ω-position orwithin a saturated ring. An effect on GABA_(A) or NMDA receptors wasdefined as a 10% or greater reversible current change from baseline thatwas statistically different from zero.

Results: Hydrocarbon moieties potentiated GABA_(A) and inhibited NMDAreceptor currents with at least some members from each functional groupmodulating both receptor types. A water solubility cut-off for NMDAreceptors occurred at 1.1 mM with a 95% CI=0.45 to 2.8 mM. NMDA receptorcut-off effects were not well correlated with hydrocarbon chain lengthor molecular volume. No cut-off was observed for GABA_(A) receptorswithin the solubility range of hydrocarbons studied.

Conclusions: Hydrocarbon modulation of NMDA receptor function exhibits amolar water solubility cut-off. Differences between unrelated receptorcut-off values suggest that the number, affinity, or efficacy ofprotein-hydrocarbon interactions at these sites likely differ.

Methods

Oocyte Collection and Receptor Expression. An ovary fromtricaine-anesthetized Xenopus laevis frogs was surgically removed usinga protocol approved by the Institutional Animal Care and Use Committeeat the University of California, Davis. Following manual disruption ofthe ovarian lobule septae, the ovary was incubated in 0.2% Type Icollagenase (Worthington Biochemical, Lakewood, N.J.) to defolliculateoocytes which were washed and stored in fresh and filtered modifiedBarth's solution composed of 88 mM NaCl, 1 mM KCl, 2.4 mM NaHCO₃, 20 mMHEPES, 0.82 mM MgSO₄, 0.33 mM Ca(NO₃)₂, 0.41 mM CaCl₂), 5 mM sodiumpyruvate, gentamycin, penicillin, streptomycin, and corrected to pH=7.4.All salts and antibiotics were A.C.S. grade (Fisher Scientific,Pittsburgh, Pa.).

Clones used were provided as a gift from Dr. R. A. Harris (University ofTexas, Austin) and were sequenced and compared to references in theNational Center for Biotechnology Information database to confirm theidentity of each gene. GABA_(A) receptors were expressed using clonesfor the human GABA_(A) α1 and the rat GABA_(A) β2 and γ2s subunits inpCIS-II vectors. Approximately 0.25-1 ng total plasmid mixturecontaining either α1, β2, or γ2 genes in a respective ratio of 1:1:10was injected intranuclearly through the oocyte animal pole and studied2-4 days later. These plasmid ratios ensured incorporation of theγ-subunit into expressed receptors, as confirmed via receptorpotentiation to 10 μM chlordiazepoxide or insensitivity to 10 μM zincchloride during co-application with GABA. In separate oocytes, glutamatereceptors were expressed using rat NMDA NR1 clones in a pCDNA3 vectorand rat NMDA NR2A clones in a Bluescript vector. RNA encoding eachsubunit was prepared using a commercial transcription kit (T7 mMessagemMachine, Ambion, Austin, Tex.) was mixed in a 1:1 ratio, and 1-10 ng oftotal RNA was injected into oocytes and studied 1-2 days later. Oocytesinjected with similar volumes of water served as controls.

GABA_(A) Receptor Electrophysiology Studies. Oocytes were studied in a250 linear-flow perfusion chamber with solutions administered by syringepump at 1.5 ml/min with gastight glass syringes and Teflon tubing.Oocyte GABA_(A) currents were studied using standard two-electrodevoltage clamping techniques at a holding potential of 80 mV using a 250μL channel linear-flow perfusion chamber with solutions administered bysyringe pump at 1.5 mL/min.

Frog Ringer's (FR) solution composed of 115 mM NaCl, 2.5 mM KCl, 1.8 mMCaCl₂), and 10 mM HEPES prepared in 18.2 MΩ H₂O and filtered andadjusted to pH=7.4 was used to perfuse oocytes. Agonist solutions alsocontained an EC10-20 of 4-aminobutanoic acid (FR-GABA) (Brosnan, et al.,Anesth Analg (2006) 103:86-91; Yang, et al., Anesth Analg (2007)105:673-679; Yang, et al., Anesth Analg (2007) 105:393-396). After FRperfusion for 5 min, oocytes were exposed to 30 sec FR-GABA followed byanother 5 min FR washout; this was repeated until stableGABA_(A)-elicited peaks were obtained. Next, FR containing a saturatedsolution of the study drug (Table 2)—or for gaseous study compounds avapor pressure equal to 90% of barometric pressure with balanceoxygen—was used to perfuse the oocyte chamber for 2 min followed byperfusion with a FR-GABA solution containing the identical drugconcentration for 30 sec. FR was next perfused for 5 min to allow drugwashout, and oocytes were finally perfused with FR-GABA for 30 sec toconfirm return of currents to within 10% of the initial baselineresponse.

Table 2

Source, purity and physical properties of study compounds. ChemicalAbstracts Service number (CAS #), molecular weight (MW), vapor pressureat 25° C. (Pvap), molar solubility in pure water at pH=7, and molecularvolume are calculated estimates (rather than measured values) referencedby SciFinder Scholar.

TABLE 2 MW P_(vap) Solubility Carbon Volume Purity Compound CAS# (amu)(mmHg) (M) (#) (Å³) Source (%) Alcohols 1-decanol 112-30-1 158.28 1.48 ×10⁻² 6.5 × 10⁻⁴ 10 317 Aldrich >99 1-undecanol 112-42-5 172.31 5.10 ×10⁻³ 1.7 × 10⁻⁴ 11 344 Acros 98 1-dodecanol 112-53-8 186.33 2.09 × 10⁻³4.1 × 10⁻⁵ 12 372 TCI 99

TABLE 2 MW P_(vap) Solubility Carbon Volume Purity Compound CAS# (amu)(mmHg) (M) (#) (Å³) Source (%) Alkanes butane 106-97-8 58.12 1.92 × 10³1.4 × 10⁻³ 4 156 Matheson 99.99 pentane 109-66-0 72.15 5.27 × 10² 4.3 ×10⁻⁴ 5 184 Aldrich >99 hexane 110-54-3 86.18 1.51 × 10² 1.2 × 10⁻⁴ 6 211Acros >99 Aldehydes octanal 124-13-0 128.21 2.07 × 10⁰ 5.4 × 10⁻³ 8 262Aldrich 99 nonanal 124-19-6 142.24  5.32 × 10⁻¹ 2.3 × 10⁻³ 9 289 Aldrich95 decanal 112-31-2 156.27  2.07 × 10⁻¹ 9.8 × 10⁻⁴ 10 316 Aldrich 98undecanal 112-44-7 170.29  8.32 × 10⁻² 4.2 × 10⁻⁴ 11 344 Aldrich 97Alkenes 1-pentene 109-67-1 70.13 6.37 × 10² 1.4 × 10⁻³ 5 176 Aldrich 991-hexene 592-41-6 84.16 1.88 × 10² 4.2 × 10⁻⁴ 6 203 Aldrich >99 Alkynes1-hexyne 693-02-7 82.14 1.35 × 10² 2.9 × 10⁻³ 6 184 Aldrich 97 1-heptyne628-71-7 96.17 4.35 × 10¹ 6.6 × 10⁻⁴ 7 212 Acros 99 1-octyne 629-05-0110.2 1.44 × 10¹ 1.9 × 10⁻⁴ 8 239 Acros 99 Amines 1-octadecanamine124-30-1 269.51  4.88 × 10⁻⁵ 1.3 × 10⁻³ 18 546 TCI 97 1-eicosanamine10525-37-8 297.56  8.96 × 10⁻⁶ 2.7 × 10⁻⁴ 20 601 Rambus 95 Benzenes1,3-dimethylbenzene 108-38-3 106.17 7.61 × 10⁰ 1.2 × 10⁻³ 8 202Aldrich >99 1,3-diethylbenzene 141-93-5 134.22 1.15 × 10⁰ 6.6 × 10⁻⁵ 10257 Fluka >99 Cycloalkanes cyclopentane 287-92-3 70.13 3.14 × 10² 3.3 ×10⁻³ 5 147 Aldrich >99 cyclohexane 110-82-7 84.16 9.37 × 10¹ 1.0 × 10⁻³6 176 Aldrich >99.7 Ethers dibutylether 142-96-1 130.23 7.10 × 10⁰ 1.6 ×10⁻² 8 277 Aldrich 99.3 dipentylether 693-65-2 158.28 1.00 × 10⁰ 3.0 ×10⁻³ 10 331 Fluka >98.5 dihexylether 112-58-3 186.33  1.48 × 10⁻¹ 5.8 ×10⁻⁴ 12 386 Aldrich 97 Esters ethyl heptanoate 106-30-9 158.24  6.02 ×10⁻¹ 5.4 × 10⁻³ 9 299 MP Bio 99 ethyl octanoate 106-32-1 172.26  2.24 ×10⁻¹ 2.1 × 10⁻³ 10 327 Aldrich >99 ethyl decanoate 110-38-3 200.32  3.39× 10⁻² 4.4 × 10⁻⁴ 12 381 TCI 98 Haloalkanes 1-fluoropentane 592-50-790.14 1.84 × 10² 3.9 × 10⁻³ 5 193 Aldrich 98 1-fluorohexane 373-14-8104.17 6.06 × 10¹ 1.2 × 10⁻³ 6 220 Acros >99 1-fluoroctane 463-11-6132.22 7.09 × 10⁰ 1.3 × 10⁻⁴ 8 275 Aldrich 98 Ketones 2-decanone693-54-9 156.27  2.48 × 10⁻¹ 3.2 × 10⁻³ 10 316 TCI >99 2-undecanone112-12-9 170.29  9.78 × 10⁻² 1.4 × 10⁻³ 11 343 Acros 98 2-dodecanone6175-49-1 184.32  3.96 × 10⁻² 5.8 × 10⁻⁴ 12 371 TCI 95 Sulfides1-(ethylthio)-hexane 7309-44-6 146.29  8.16 × 10⁻¹ 2.8 × 10⁻³ 8 289Pfaltz 97 1-(ethylthio)-octane 3698-94-0 174.35  1.08 × 10⁻¹ 5.0 × 10⁻⁴10 344 Pfaltz 97 Thiols 1-pentanethiol 110-66-7 104.21 1.42 × 10¹ 1.5 ×10⁻³ 5 207 Aldrich 98 1-hexanethiol 111-31-9 118.24 4.50 × 10⁰ 5.1 ×10⁻⁴ 6 235 TCI 96

NMDA Receptor Electrophysiology Studies. Methods for measurement ofwhole-cell NMDA receptor currents have been described (Brosnan, et al.,Br J Anaesth (2008) 101:673-679; Brosnan, et al., Anesth Analg (2011)112:568-573). Briefly, baseline perfusion solutions were the same as forGABA_(A) with the substitution of equimolar BaCl₂ for calcium salts andthe addition of 0.1 mM EGTA; this constituted barium frog Ringer'ssolution (BaFR). Agonist solutions for NMDA studies also contained 0.1mM glutamate (E) and 0.01 mM glycine (G) to constitute a BaFREGsolution.

The syringe pump and perfusion chamber apparatus as well as the clampholding potential and baseline-agonist exposure protocols were identicalto that described for the GABA_(A) studies. The same test compounds,concentrations, and preparative methods were used in NMDA voltage clampstudies as in the GABA_(A) voltage clamp studies (Table 2).

Response Calculations and Data Analysis. Modulating drug responses werecalculated as the percent of the control (baseline) peak as follows:100·I_(D)/I_(B), where I_(D) and I_(B) were the peak currents measuredduring agonist+drug and agonist baseline perfusions, respectively. Whenpresent, direct receptor activation by a drug was similarly calculatedas a percent of the agonist response. Average current responses for eachdrug and channel were described by mean±SD. A lack of receptor response(cut-off) was defined as a <10% change from baseline current that wasstatistically indistinguishable from zero using a two-tailed Studentt-test. Hence, drug responses ≥110% of the baseline peak showedpotentiation of receptor function, and drug responses ≤90% of thebaseline peak showed inhibition of receptor function.

The log₁₀ of the calculated solubility (log₁₀ S) for compoundsimmediately below and above the cut-off for each hydrocarbon functionalgroup were used to determine the receptor cut-off. For each hydrocarbon,there was a “grey area” of indeterminate solubility effect (FIG. 3)between sequentially increasing hydrocarbon chain length. Meansolubility cut-offs were calculated as the average log₁₀ S for the leastsoluble compound that modulated receptor function and the most solubleneighboring compound for which no effect was observed. From this result,a 95% confidence interval for log₁₀ S was calculated for receptorsolubility cut-offs.

Results

Hydrocarbon effects on NMDA and GABA_(A) receptors are summarized inTable 3, and sample recordings are presented in FIG. 3. All of thecompounds tested positively modulated GABA_(A) receptor function, and afew of the 5-to-6 carbon compounds caused mild direct GABA_(A) receptoractivation, particularly the 1-fluoroalkanes and thiols. Mild directreceptor activation also occurred with dibutylether. With the exceptionof the aldehydes, alkynes, and cycloalkanes, GABA_(A) receptorinhibition tended to decrease with increasing hydrocarbon chain length.No water solubility cut-off effect was observed for GABA_(A) receptorsfor the compounds tested.

Table 3

Mean responses (±SEM) produced by 14 different functional groups on NMDAand GABA_(A) receptor modulation, expressed as a percent of the controlagonist peak, using standard two-electrode voltage clamp techniques with5-6 oocytes each. The % Direct Effect is the drug response withoutco-administration of the receptor agonist. The % Agonist Effect is thedrug response with co-administration of agonist (glutamate and glycinefor NMDA receptors; γ-aminobutyric acid for GABA_(A) receptors). TheDrug Response denotes inhibition (−) for drug+agonist responses lessthan the control agonist peak, potentiation (+) for drug+agonistresponses greater than the control agonist peak, and no response (0) fordrug+agonist responses that differ by <10% from the control agonistpeak.

TABLE 3 NMDA GABA_(A) % Direct % Agonist Drug % Direct % Agonist DrugCompound Effect Effect Response Effect Effect Response Alcohols1-decanol none 70 ± 3 — none 386 ± 20 + 1-undecanol none 101 ± 2  0 none181 ± 13 + 1-dodecanol none 98 ± 1 0 none 177 ± 4  + Alkanes butane none 7 ± 2 — none 623 ± 68 + pentane none 94 ± 3 0 none 321 ± 10 + hexanenone 100 ± 1  0 none 129 ± 5  + Aldehydes octanal none 71 ± 3 — 6 ± 3357 ± 20 + nonanal none 104 ± 2  0 none 219 ± 29 + decanal none 97 ± 3 0none 159 ± 5  + undecanal none 97 ± 8 0 none 299 ± 29 + Alkenes1-pentene none 69 ± 1 — 2 ± 3 453 ± 38 + 1-hexene none 97 ± 0 0 none 132± 2  + Alkynes 1-hexyne none 41 ± 6 — 5 ± 2 418 ± 21 + 1-heptyne none 68 ± 10 — none 172 ± 8  + 1-octyne none 96 ± 2 0 none 259 ± 11 + Amines1-octadecanamine none 73 ± 4 — none 146 ± 5  + 1-eicosanamine none 108 ±1  0 none 166 ± 7  + Benzenes 1,3-dimethylbenzene none 58 ± 3 — none 366± 21 + 1,3-diethylbenzene none 101 ± 2  0 none 305 ± 24 + Cycloalkanescyclopentane none 83 ± 2 — 3 ± 2 196 ± 11 + cyclohexane none 101 ± 2  0none 421 ± 17 + Ethers dibutylether none 59 ± 4 — 14 ± 13 347 ± 33 +dipentylether none 97 ± 2 0 none 211 ± 9  + dihexylether none 112 ± 4  0none 113 ± 1  + Esters ethyl heptanoate none 78 ± 3 — none 370 ± 34 +ethyl octanoate none 90 ± 1 — none 285 ± 18 + ethyl decanoate none 98 ±1 0 none 137 ± 2  + Haloalkanes 1-fluoropentane none 76 ± 2 — none 539 ±35 + 1-fluorohexane none 101 ± 1  0 11 ± 4  207 ± 13 + 1-fluoroctanenone 98 ± 1 0 none 182 ± 18 + Ketones 2-decanone none 81 ± 1 — none 476± 52 + 2-undecanone none 98 ± 2 0 none 230 ± 16 + 2-dodecanone none 97 ±3 0 none 325 ± 30 + Sulfides 1-(ethylthio)-hexane none 87 ± 1 — none 350± 57 + 1-(ethylthio)-octane none 101 ± 1  0 none 120 ± 3  + Thiols1-pentanethiol none 85 ± 4 — 22 ± 8  466 ± 57 + 1-hexanethiol none 102 ±3  0 8 ± 2 290 ± 41 +

In contrast, NMDA receptors currents were decreased by the shorterhydrocarbons within each functional group (Table 2), but lengthening thehydrocarbon chain eventually produced a null response—a cut-off effect.No direct hydrocarbon effects on NMDA receptor function were detected inthe absence of glutamate and glycine agonist.

The cut-off effect for NMDA receptor current modulation was associatedwith a hydrocarbon water solubility of 1.1 mM with a 95% confidenceinterval between 0.45 mM and 2.8 mM (FIG. 4). More soluble hydrocarbonsconsistently inhibited NMDA receptor currents when applied at saturatedaqueous concentrations, and hydrocarbons below this range had noappreciable effect on NMDA receptor function. Moreover, during thecourse of the study, water solubility was sufficiently predictive of anNMDA receptor cut-off so as to require identify and testing of onlysingle pair of compounds bracketing this critical solubility value, asoccurred with the alkenes, amines, cyclic hydrocarbons, andsulfur-containing compounds.

Increasing hydrocarbon chain length decreases water solubility, but alsoincreases molecular size. However, when graphed as a function of eithercarbon number (FIG. 5) or molecular volume (FIG. 6), the observed NMDAreceptor cut-off effects show no consistent pattern. For example, then-alkanes, 1-alkenes, and 1-alkynes show progressive lengthening of thehydrocarbon chain cut-off, presumably as a result of the increasingaqueous solubility conferred by the double and triple carbon bonds,respectively. There was also tremendous variation in molecular size ofcompounds exhibiting NMDA receptor cut-off Alkanes exhibited NMDAreceptor cut-off between butane and pentane, respectively 4 and 5carbons in length, whereas the primary amines exhibited cut-off between1-octadecanamine and 1-eicosanamine, respectively 18 and 20 carbons inlength. As expected, the molecular volume of these compounds associatedwith NMDA receptor cut-off is also quite different, with the primaryamine being over 3 times larger than the alkane.

Discussion

NMDA receptor modulation is associated with an approximate 1.1 mM watersolubility cut-off (FIG. 4). In contrast, GABA_(A) receptors potentiatedall studied compounds, suggesting that either a GABA_(A) cut-off occursat a lower water solubility value or possibly that GABA_(A) receptorslack such a cut-off. Increasing a single hydrocarbon length to find areceptor cut-off effect introduces confounding factors of carbon numberand molecular volume that could in turn be responsible for the cut-offeffect (Eger, et al., Anesth Analg (1999) 88:1395-1400; Jenkins, JNeurosci (2001) 21:RC136; Wick, Proc Natl Acad Sci USA (1998)95:6504-6509; Eger, Anesth Analg (2001) 92:1477-1482). An aggregatecomparison of cut-off values for all functional groups as a function ofcarbon number (FIG. 5) or molecular volume (FIG. 6) shows no discerniblepattern, suggesting that these physical properties are unlikely theprimary limiting factors for drug-receptor modulation.

Nonetheless, although the correlation between cut-off and molar watersolubility is very good, it is not perfect. Some variability is duesimply to the lack of compounds of intermediate solubility within afunctional group series. For example, pentanethiol inhibited NMDAreceptors, whereas the 1-carbon longer hexanethiol did not (Table 3).This pre-cut-off thiol is nearly 3-times more soluble in water than itspost-cut-off cognate; yet it is not possible to obtain a more narrowlydefined cut-off delineation for 1-thiols. Even larger variability wasobserved with the dialkylbenzene series, to which 1 additional carbonwas added to each 1- and 3-alkyl group. The solubility ratio between theNMDA antagonist 1,3-dimethylbenzene and its cut-off cognate1,3-diethylbenzene is more than 18 (Table 3).

Variability about the molar water solubility NMDA receptor cut-off mayalso have arisen from the use of calculated, rather than measured,values for hydrocarbon molar water solubility. Aqueous solubility isdifficult to measure accurately, particularly for poorly solublesubstances. Calculated solubilities are more accurate for smalluncharged compounds, but still can have an absolute error within 1 logunit (Delaney, et al., Drug Discov Today (2005) 10:289-295). However,even predicted values for nonpolar n-alkanes may show large deviationsfrom experimental data as the hydrocarbon chain length increases(Ferguson, J Phys Chem B (2009) 113:6405-6414).

Furthermore, the molar solubility values used in the present study werecalculated for pure water at 25° C. and at pH=7.0. These were not theconditions under which drug-receptor effects were studied. Ringer'soocyte perfusates contained buffers and physiologic concentrations ofsodium, potassium, and chloride resulting in a 250 mOsm solution. Thesolubility of haloether and haloalkane anesthetic vapors vary inverselywith osmolarity (Lerman, et al., Anesthesiology (1983) 59:554-558), asdo the water-to-saline solubility ratio of benzenes, amines, and ketones(Long, et al., Chem Rev (1952) 51:119-169). The presence of salts couldhave caused overestimation of aqueous solubility for some compounds whenusing values calculated for pure water. Likewise, solubility is alsotemperature-dependent. Studies were conducted at 22° C.; solubility ofgases in water should be greater than values calculated at 25° C. Incontrast, most solutes used in the present study have negative enthalpyfor dissolution (Abraham, et al., J Am Chem Soc (1982) 104:2085-2094),so solubility should be decreased at the lower ambient temperature. Thereverse should occur for exothermic solutions, as predicted by the LeChatelier principle. As for hydronium ion concentration, the solubilityof most study compounds is trivially affected at pH values between7-to-8. However, hydrocarbons containing an amine group have pKa valuesthat are closer to physiologic pH, and the calculated aqueous solubilityof 1-eicosanamine and 1-octadecanamine (Table 2) decreases by about 66%as pH increases from 7 to 8. Calculated molar water solubilities for theamines in this study were probably modestly overestimated at aphysiologic pH equal to 7.4.

Despite these inaccuracies inherent in calculated rather thanexperimentally measured values, an association between molar watersolubility and NMDA receptor modulation cut-off remains evident.Anesthetics exhibit low-affinity binding on receptors; these weakinteractions are inconsistent with an induced fit binding. Rather,anesthetics likely bind to pre-existing pockets and surfaces on orwithin the protein (Trudell, et al., Br J Anaesth (2002) 89:32-40). Acritical water solubility for modulation implies that criticalmodulation sites are either hydrophilic or amphiphilic. Hydrocarbons actas hydrogen bond donors—or in the case of electrophiles, as hydrogenbond acceptors—with amino acid residues on anesthetic-sensitivereceptors, resulting in displacement of water molecules from thesebinding pockets and alteration of protein function (Bertaccini, et al.,Anesth Analg (2007) 104:318-324; Abraham, et al., J Pharm Sci (1991)80:719-724; Streiff, et al., J Chem Inf Model (2008) 48:2066-2073).These low energy anesthetic-protein interactions are postulated to beenthalpically favorable since the displaced water molecules should bebetter able to hydrogen bond with like molecules in the bulk solventrather than with amino acids (Bertaccini, et al., Anesth Analg (2007)104:318-324; Streiff, et al., J Chem Inf Model (2008) 48:2066-2073).Halothane and isoflurane both have been shown to bind in wateraccessible pockets formed between α-helices in δ-subunits of thenicotinic acetylcholine receptor (Chiara, et al., Biochemistry (2003)42:13457-13467), a member of the 4-transmembrane receptor superfamilythat includes the GABA_(A) receptor. Models of nicotinic acetylcholinereceptors and GABA_(A) receptors further suggest that endogenous agonistor anesthetic binding might increase water accumulation in hydrophilicpockets and increase the number and accessibility of hydrophilic sitesthat are important for channel gating (Willenbring, et al., Phys ChemChem Phys (2010) 12:10263-10269; Williams, et al., Biophys J (1999)77:2563-2574). However, molecules that are insufficiently water solublemay not be able to displace enough water molecules at enough criticalsites in order to modulate channel function.

NMDA receptor modulation by inhaled anesthetics such as isoflurane,xenon, and carbon dioxide occurs—at least in part—at hydrophilic agonistbinding sites (Brosnan, et al., Anesth Analg (2011) 112:568-573;Dickinson, et al., Anesthesiology (2007) 107:756-767). Yet despiteevidence that hydrophilic interactions are important to hydrocarbonmodulation of anesthetic-sensitive receptors, the minimum hydrocarbonhydrophilicity required to exert anesthetic-like effects is differentbetween NMDA and GABA_(A) receptors. As these receptors belong todifferent and phylogenetically distinct superfamilies, it seems likelythat either the number of displaced water molecules required to effectmodulation and/or the relative affinities of the hydrocarbon versuswater molecule for a critical hydrophilic protein pocket and/or thenumber of hydrophilic sites necessary for allosteric modulation shouldalso be different between proteins. Put another way, there is a minimumnumber of hydrocarbon molecules—no matter the type—that is required tointeract with NMDA receptors to alter ion channel conductance, and thisnumber is significantly greater than that necessary to alter GABA_(A)receptor ion channel conductance. Implied is that other ion channelsshould exhibit hydrocarbon cut-off effects that correlate with molarwater solubility, and these solubility cut-off values will likely bemore similar between channels having a common phylogeny than cut-offvalues between distantly or unrelated proteins.

Hydrocarbons below the water solubility cut-off presumably haveinsufficient molecules in the aqueous phase to successfully compete withwater at hydrophilic modulation or transduction sites on a receptoralter its function. Likewise, transitional compounds and nonimmobilizerspredicted by the Meyer-Overton correlation to produce anesthesia eitherhave lower than expected potency or lack anesthetic efficacy altogether.And like NMDA cut-off hydrocarbons in the present study, transitionalcompounds and nonimmobilizers all share a common property of low aqueoussolubility (Eger E I, 2nd. Mechanisms of Inhaled Anesthetic Action In:Eger E I, 2nd, ed. The Pharmacology of Inhaled Anesthetics. IL, USA:Baxter Healthcare Corporation, 2002; 33-42). Nonimmobilizers such as1,2-dichlorohexafluorocyclobutane fail to depress GABA_(A)-dependentpyramidal cells (Perouansky, et al., Anesth Analg (2005) 100:1667-1673)or NMDA-dependent CA1 neurons (Taylor, et al., Anesth Analg (1999)89:1040-1045) in the hippocampus, and likely lack these effectselsewhere in the central nervous system. With decreasing watersolubility, there is differential loss of receptor effects—such asoccurred with NMDA receptors versus GABA_(A) receptors in the presentstudy. The anesthetic cut-off effect in whole animal models correlateswith agent water solubility, and might be explained by the loss of oneor more anesthetic-receptor contributions to central nervous systemdepression. Conversely, receptor molar water solubility cut-off valuesmay be used to define those ion channels that are sine qua non forvolatile anesthetic potency. Inhaled agents likely act via low affinityinteractions with multiple cell receptors and ion channels to decreaseneuronal excitability in the brain and spinal cord, but a loss orinadequate contribution from certain targets—perhaps GABA_(A) or glycinereceptors—as water solubility decreases may render a drug anonimmobilizer. Additionally, agents having a water solubility below thecut-off value for some anesthetic-sensitive receptors may also produceundesirable pharmacologic properties, such as seizures following theloss of GABA_(A) receptor modulation (Raines, Anesthesiology (1996)84:663-671). In contrast, NMDA receptors can contribute to immobilizingactions of conventional volatile anesthetics,43 but they are not as ageneral principle essential for inhaled anesthetic action since an agentlike pentane does not modulate NMDA receptors—even at a saturatedaqueous concentration (Table 3)—yet has a measurable minimum alveolarconcentration (Liu, et al., Anesth Analg (1993) 77:12-18; Taheri, etal., Anesth Analg (1993) 77:7-11).

Although only water solubility was predictive of NMDA receptor cut-off,size and shape nonetheless must be able influence this effect. Most ofthe hydrocarbons examined in the present study had functional groupslocated on the 1- or 2-carbon position. However, the ethers were all1,1′-oxybisalkanes; each member of the ether consisted of symmetrical1-carbon additions to alkyl groups on either side of the oxygen atom(Table 2). Hence this electron-rich oxygen atom allowing hydrogenbonding with water molecules or amino acid residues with strong partialpositive charges lies buried in the middle of the ether. Consequently,for hydrocarbons with equivalent molar water solubilities, it may bemore difficult for dialkyl ether to form hydrogen bonds in hydrophilicreceptor pockets compared to a long primary amine (Table 2) that mightmore easily insert its nucleophilic terminus into the anesthetic-bindingpocket while the long hydrophobic carbon chain remains in the lipidmembrane. This may explain why ethers in this study appear to exhibit anNMDA cut-off that is slightly greater than hydrocarbons with otherfunctional groups. Perhaps if a methyl-alkyl ether series were usedinstead of a dialkyl ether series, the apparent molar water solubilitycut-off for this group would have been lower.

As the hydrocarbon chain lengthened within any functional group, theefficacy of GABA_(A) receptor modulation also tended to increase. Thisis consistent with the Meyer-Overton prediction of increased anestheticpotency as a function of increasing hydrophobicity (Mihic, et al., MolPharmacol (1994) 46:851-857; Horishita, et al., Anesth Analg (2008)107:1579-1586). However, the efficacy by which NMDA receptors wereinhibited by hydrocarbons prior to the cut-off varied greatly betweenfunctional groups. Most compounds caused about 25-to-40% inhibition ofNMDA receptor currents. However, the alkane n-butane almost completelyinhibited NMDA receptor currents prior to cut-off, whereas the thiol1-pentanethiol caused only 15% NMDA receptor current inhibition. Sincesolubility values are discontinuous within a hydrocarbon series, it isnot possible to evaluate changes in modulation efficacy as solubilityasymptotically approaches a cut-off within a hydrocarbon functionalgroup series. Perhaps agents that are closer to the critical molar watersolubility required for receptor modulation begin to lose potencydespite increasing drug lipophilicity. If so, differences in NMDAreceptor efficacy may reflect the relative difference between thistheoretical critical molar water solubility and the aqueous solubilityof the pre-cut-off test agent.

Finally, discrete and distinct water solubility cut-off values foranesthetic-sensitive receptors offer the possibility of astructure-activity relationship that may aid new pharmaceutical design.Anesthetics produce a number of desirable effects, such as analgesia andamnesia, and a number of side effects, such as hypotension andhypoventilation. Different pharmacodynamic properties are likelymediated by different cell receptors or channels or combinationsthereof. Thus, by modifying a compound to decrease its water solubilitybelow the NMDA receptor cut-off, absolute specificity for GABA_(A)versus NMDA receptors may be obtained and those side-effects mediated byNMDA receptor inhibition should be reduced or eliminated. Conversely,highly insoluble agents could be modified to increase the molar watersolubility above the NMDA cut-off in order to add desirablepharmacologic effects from this receptor, provided that the immobilizingversus NMDA receptor median effective concentrations are notsufficiently different as to maintain relative receptor specificity. Atthe same time, differential cut-off values suggest an important limit todrug design. It will probably not be possible to design an anestheticwith low-affinity receptor binding that exhibits absolute specificityfor NMDA receptors while having no effect on GABA_(A) receptors up to asaturating aqueous concentration. Only if the minimum alveolarconcentration and the anesthetic potency at NMDA receptors are muchgreater than the anesthetic potency at GABA_(A) receptors might relativeanesthetic specificity for NMDA receptors be achieved.

Example 2 1,1,2,2,3,3,4-Heptafluorocyclopentane (CAS #15290-77-4)Induces Anesthesia

All known inhalation anesthetics modulate multiple unrelated anestheticreceptors, such as transmembrane-3 (TM3) receptors, transmembrane-4(TM4) receptors, or both TM3 and TM4 receptors. We tested a series ofhomologous n-alcohols, n-alkanes, n-alkenes, n-alkynes, n-aldehydes,primary amines, 1-alkylfluorides, dialkyl ethers, alkyl benzenes,esters, haloalkanes, ketones, sulfides, and thiols that differed only by1 or 2 carbon chain lengths. We studied the effects of these drugs onNMDA receptors (a member of the TM3 superfamily) and GABA_(A) receptors(a member of the TM4 superfamily) at saturating drug concentrations inan oocyte two-electrode voltage clamp model. For GABA_(A) versus NMDAreceptors, we found that there is no correlation between specificity andvapor pressure, carbon chain length, or molecular volume. However, thereexists a water solubility-specificity cut-off value equal to about 1.1mM with a 95% confidence interval between about 0.4 and about 2.9 mM(calculated molar solubility in water at pH=7). Compounds more solublethan this threshold value can negatively modulate NMDA receptors andpositively modulate GABA_(A) receptors. Compounds less soluble than thisthreshold value only positively modulate GABA_(A) receptors. We havealso identified approximate water solubility cut-off values for glycinereceptors, K2P channels, and voltage-gated sodium channels.

The above-described structure activity relationship was used to identifycandidate anesthetics, predict the receptor effect profile of unknowncandidate anesthetics, and provide the means by which known anestheticscan be modified to change their water solubility and thus theirpharmacologic effect profile. Using the above method, we have identifiedseveral candidate cyclic halogenated hydrocarbon and cyclic halogenatedheterocycles that are predicted to modulate GABA_(A) receptors,including agents that show absolute selectivity for GABA_(A) vs. NMDAreceptors (i.e., that potentiate GABA_(A) receptors without inhibitingNMDA receptors). We identified 1,1,2,2,3,3,4-heptafluorocyclopentane(HFCP) (CAS #15290-77-4), and predicted by its solubility that it wouldselectively modulate GABA_(A) but not NMDA receptors and exert a generalanesthetic effect (it has until this time never been evaluated inbiological systems for narcotic effects). HFCP is colorless, odorless,nonflammable, stable⋅in soda lime, and has sufficient vapor pressure todeliver via inhalation.

HFCP caused loss of righting reflex (a surrogate measure ofunconsciousness) in 4 healthy ND4 mice at 1.0±0.2 (mean±SD) percent of 1atmosphere. This odorless agent caused no excitement or coughing duringanesthetic induction. After 2 hours of anesthesia, mice were awake afterabout 1 minute of discontinuing HFCP administration. Histopathology ofheart, lung, kidney and liver tissues collected 2 days later revealed noevidence of inflammation or toxicity. As predicted by its watersolubility, 1,1,2,2,3,3,4-heptafluorocyclopentane potentiates GABA_(A),glycine, and some inhibitory potassium channels in vitro, but has noeffect on NMDA receptors up to a saturating aqueous concentration.Despite a lack of NMDA receptor effects,1,1,2,2,3,3,4-heptafluorocyclopentane is able to produce the desiredpharmacologic endpoints of unconsciousness and immobility that appearssimilar to desirable effects produced by conventional agents.

To our knowledge, no new inhaled anesthetics are currently underdevelopment because of an incomplete understanding of the mechanisms ofaction and activity-structure relationships of these agents. Inhalationanesthetics have among the lowest therapeutic indices (low safetymargin) of drugs in routine clinical use; there is a need to developnewer and safer agents. We have identified a physical property (molarwater solubility) that is important to determining whether an anestheticcan modulate channels or receptors that contribute to immobility andamnesia. We have applied this knowledge in order to identify a novelvolatile anesthetic of clinical use (HFCP) which also lacks NMDAreceptor modulation.

Example 3 1,1,2,2,3,3,4,5-Octafluorocyclopentane (CAS #828-35-3) InducesAnesthesia

1,1,2,2,3,3,4,5-octafluorocyclopentane (CAS #828-35-3) caused a loss ofrighting reflex in 4 healthy Sprague-Dawley rats at a concentration of3.3±0.4 (mean±SD) percent of 1 atmosphere. This agent has a faint butpleasant odor and induced anesthesia very rapidly without excitement orcoughing. After discontinuing the agent, rats were awake and ambulatoryin less than 1 minute. As predicted by its water solubility,1,1,2,2,3,3,4,5-octafluorocyclopentane potentiates GABA_(A), glycine,and some inhibitory potassium channels in vitro, but has no effect onNMDA receptors up to a saturating aqueous concentration. Despite a lackof NMDA receptor effects, 1,1,2,2,3,3,4,5-octafluorocyclopentane is ableto produce the desired pharmacologic endpoints of unconsciousness andimmobility that appears similar to desirable effects produced byconventional agents.

Example 4 Perfluorotetrahydropyran (CAS #355-79-3) Induces Anesthesia

Perfluorotetrahydropyran (CAS #355-79-3) caused a loss of rightingreflex in mice at a concentration of 1-10%.

Example 5 2,2,3,3,4,5- Hexafluorotetrahydro-5-(Trifluoromethyl)-FuranInduces Anesthesia

2,2,3,3,4,5- hexafluorotetrahydro-5-(trifluoromethyl)-furan (a mixtureof the isomers from CAS #133618-59-4 and CAS #133618-49-2) caused a lossof righting reflex in mice at a concentration of 1-10%.

Example 6 Synthesis Schemes

General schemes for the synthesis of the halogenated anesthesiacompounds described herein are known in the art. References describingthe synthesis schemes generally and for the specific compounds aresummarized in Table 4, below.

TABLE 4 Compound Published Reference GENERAL SYNTHETIC Chambers, RichardD. Fluorine in Organic Chemistry. WileyBlackwell. FLUOROCHEMISTRYTEXTBOOKS 2004. ISBN: 978-1405107877. z z Iskra, Jernej. HalogenatedHeterocycles: Synthesis, Application and Environment (Topics inHeterocyclic Chemistry). Springer. 2012. ISBN: 978-3642251023 Gakh,Andrei and Kirk, Kenneth L. Fluorinated Heterocycles (ACS SymposiumSeries). American Chemical Society. 2009. ISBN: 978- 0841269538 ALCOHOLS1351959-82-4 Methanol, 1-fluoro-1-[2,2,2- trifluoro-1-(trifluoromethyl)ethoxy]- 14115-49-2 1-Butanol, 4,4,4-trifluoro-Mochalina, E. P.; Dyatkin, B. L.; Galakhov, I. V.; Knunyants, I. L.Doklady 3,3-bis(trifluoromethyl)- Akademii Nauk SSSR (1966), 169(6),1346-9. Delyagina, N. I.; Pervova, E. Ya.; Knunyants, I. L. IzvestiyaAkademii Nauk SSSR, Seriya Khimicheskaya (1972), (2), 376-80. 3056-01-71-Butanol, 1,1,2,2,3,3,4,4,4- nonafluoro- 782390-93-6 1-Butanol,2,2,3,4,4,4- hexafluoro-3- (trifluoromethyl)- 90999-87-4 1-Butanol,3,4,4,4- tetrafluoro-3- (trifluoromethyl)- 313503-66-1 1-Pentanol,1,1,4,4,5,5,5- heptafluoro- 57911-98-5 1-Pentanol,1,1,2,2,3,3,4,4,5,5,5- undecafluoro- DIETHERS 362631-92-3 Ethane,1,1-trifluoro-1,2- bis(trifluoromethoxy)- 115395-39-6 Ethane,1,1,1,2-tetrafluoro- Venturini, Francesco; Metrangolo, Pierangelo;Resnati, Giuseppe; 2,2-bis(trifluoromethoxy)- Navarrini, Walter;Tortelli, Vito. Chimica Oggi (2008), 26(4), 36-38. Navarrini, Walter;Venturini, Francesco; Sansotera, Maurizio; Ursini, Maurizio; Metrangolo,Pierangelo; Resnati, Giuseppe; Galimberti, Marco; Barchiesi, Emma;Dardani, Patrizia. Journal of Fluorine Chemistry (2008), 129(8),680-685. Adcock, James L.; Robin, Mark L.; Zuberi, Sharique. Journal ofFluorine Chemistry (1987), 37(3), 327-36. 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L.; Lagow, R. J. Journal ofthe American Chemical Society (1974), 96(24), 7588. Abe. Takashi;Nagase, Shunji; Baba, Hajime. Bulletin of the Chemical Society of Japan(1973), 46(8), 2524-7. Sianesi, Dario; Fontanelli, Renzo; Grazioli,Alberto. Ger. Often. (1972), DE 2111696 A 19720127. DIOXOLANES344303-08-8 1,3-Dioxolane, 2,4,4,5- tetrafluoro-5- (trifluoromethyl)-344303-05-5 1,3-Dioxolane, 2-chloro- 4,4,5-trifluoro-5-(trifluoromethyl)- 269716-57-6 1,3-Dioxolane, 4,4,5,5- Kawa, Hajim;Takubo, Seiji. Jpn. Kokai Tokkyo Koho (2000), JP tetrafluoro-2-2000143657 A 20000526. (trifluoromethyl)- 238754-29-5 1,3-Dioxolane,4-chloro- Russo, Antonio; Navarrini, Walter. Eur. Pat. Appl. (1999), EP937720 A1 2,2,4-trifluoro-5- 19990825. (trifluoromethyl)- Russo,Antonio; Navarrini, Walter. Journal of Fluorine Chemistry (2004),125(1), 73-78. 162970-78-7 1,3-Dioxolane, 4,5-dichloro- Navarrini, W.;Bragante, L; Fontana, S.; Tortelli, V.; Zedda, A. 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Journal oftetrafluoro-5- Fluorine Chemistry (1982), 21(2), 107-32.(trifluoromethyl)-, trans- (9Cl) 85036-65-3 1,3-Dioxolane, 2,4,4,5-Muffler, Herbert; Siegemund, Guenter; Schwertfeger, Werner. Journal oftetrafluoro-5- Fluorine Chemistry (1982), 21(2), 107-32.(trifluoromethyl)-, cis- (9Cl) 85036-60-8 1,3-Dioxolane, 2-chloro-Muffler, Herbert; Siegemund, Guenter; Schwertfeger, Werner. Journal of4,4,5-trifluoro-5- Fluorine Chemistry (1982), 21(2), 107-32.(trifluoromethyl)-, trans- (9Cl) 85036-57-3 1,3-Dioxolane, 2-chloro-Muffler, Herbert; Siegemund, Guenter; Schwertfeger, Werner. Journal of4,4,5-trifluoro-5- Fluorine Chemistry (1982), 21(2), 107-32.(trifluoromethyl)-, cis- (9Cl) 85036-55-1 1,3-Dioxolane, 2,2-dichloro-Muffler, Herbert; Siegemund, Guenter; Schwertfeger, Werner. Journal of4,4,5,5-tetrafluoro- Fluorine Chemistry (1982), 21(2), 107-32.76492-99-4 1,3-Dioxolane, 4,4,5- Siegemund, Guenter; Muffler, Herbert.Ger. Offen. (1980), DE 2906447 trifluoro-5-(trifluoromethyl)- A119800904. Muffler, Herbert; Siegemund, Guenter; Schwertfeger, Werner.Journal of Fluorine Chemistry (1982), 21(2), 107-32. 64499-86-11,3-Dioxolane, 4,4-difluoro- 2,2-bis(trifluoromethyl)- 64499-85-01,3-Dioxolane, 4,5-difluoro- 2,2-bis(trifluoremethyl)-, cis- (9Cl)64499-66-7 1,3-Dioxolane, 4,5-difluoro- 2,2-bis(trifluoromethyl)-,trans- (9Cl) 64499-65-6 1,3-Dioxolane, 4,4,5- Anton, Douglas Robert;Farnham, William Brown; Hung, Ming Hong; trifluoro-2,2- Mckinney, RonaldJames; Resnick, Paul Raphael. PCT Int. Appl. (1991),bis(trifluoromethyl)- WO 9109025 A2 19910627. 55135-01-8 1,3-Dioxolane,2,4,4,5,5- Berenblit, V. V.; Dolnakov, Yu. P.; Sass, V. P.; Senyushov,L. N.; pentafluoro-2- Sokolov, S. V. Zhurnal Organicheskoi Khimii(1974), 10(10), 2031-5. (trifluoromethyl)- Berenblit, V. V.; Dolnakov,Yu. P.; Davydov, G. A.; Grachev, V. I.; Sokolov, S. V. ZhurnalPrikladnoi Khimii (Sankt-Peterburg, Russian Federation) (1975), 48(10),2206-10. 21297-65-4 1,3-Dioxolane, 2,2,4,4,5,5- Prager, Julianne H.Journal of Organic Chemistry (1966), 31(2), 392-4. hexafluoro-Throckmorton, James R. Journal of Organic Chemistry (1969), 34(11),3438-40. Sianesi, Dario; Fontanelli, Renzo; Grazioli, Alberto. Ger.Offen. (1972), DE 2111696 A 19720127. Berenblit, V. V.; Dolnakov, Yu.P.; Davydov, G. A; Grachev, V. I.; Sokolov, S. V. Zhurnal PrikladnoiKhimii (Sankt-Peterburg, Russian Federation) (1975), 48(10), 2206-10.Berenblit, V. V.; Dolnakov, Yu. P.; Sass, V. P.; Senyushov, L. N.;Sokolov, S. V. Zhurnal Organicheskoi Khimii (1974), 10(10), 2031-5.Navarrini, Walter; Fontana, Simonetta; Montanari, Vittorio. Eur. Pat.Appl. (1991), EP 460948 A2 19911211. Navarrini, W.; Bragante, L.;Fontana, S.; Tortelli, V.; Zedda, A. Journal of Fluorine Chemistry(1995), 71(1), 111-17. 19701-22-5 1,3-Dioxolane, 2,2,4,4,5- Navarrini,Walter; Fontana, Simonetta; Montanari, Vittorio. Eur. Pat.pentafluoro-5- Appl. (1991), EP 460948 A2 19911211. (trifluoromethyl)-Navarrini, W.; Bragante, L.; Fontana, S.; Tortelli, V.; Zedda, A.Journal of Fluorine Chemistry (1995), 71(1), 111-17. CYCLOPENTANES362014-70-8 Cyclopentane, 5-chloro- Imura, Hideaki; Takada, Naokado;Komata, Takeo. Jpn. Kokai Tokkyo 1,1,2,2,3,3,4,4-octafluoro- Koho(2001), JP 2001261594 A 20010926. 773-17-1 Cyclopentane, Heitzman, R.J.; Patrick, C. R.; Stephens, R.; Tatlow, J. C. Journal of the1,1,2,2,3,4,4,5-octafluoro- Chemical Society (1963), 281-9. 828-35-3Cyclopentane, Sekiya, Akira; Yamada, Toshiro; Watanabe, Kazunori. PCTInt. Appl. 1,1,2,2,3,3,4,5-octafluoro- (1996), WO 9600707 A1 19960111.Sekya, Akira; Yamada, Toshiro; Watanabe, Kazunori. Jpn. Kokai TokkyoKoho (1996), JP 08143487 A 19960604. 3002-03-7 Cyclopentane,1,1,2,3,3,4,5-heptafluoro- 149600-73-7 Cyclopentane, Rao, Velliyur NottMallikarjuna; Weigert, Frank Julian; Krespan, Carl1,1,2,2,3,3,4,4-octafluoro- George. PCT Int. Appl. (1993), WO 9305002 A219930318. 1765-23-7 Cyclopentane, Heitzman, R. J.; Patrick, C. R.;Stephens, R.; Tatlow, J. C. Journal of the 1,1,2,2,3,4,5-heptafluoro-Chemical Society (1963), 281-9. Burdon, J.; Hodgins, T. M.; Stephens,R.; Tatlow, J. C. Journal of the Chemical Society (1965), (April),2382-91. Yamada, Toshiro; Sugimoto, Tatsuya. Jpn. Kokai Tokkyo Koho(1999), JP 11292807 A 19991026. 699-38-7 Cyclopentane, 1,1,2,3,4,5-hexafluoro- 15290-77-4 Cyclopentane, Otsuki, Noriyasu. Petrotech (Tokyo,Japan) (2005), 28(7), 489-493. 1,1,2,2,3,3,4-heptafluoro- Takada,Naokado; Hirotsu, Miki; Komata, Takeo. Jpn. Kokai Tokkyo Koho (2002), JP2002241325 A 20020828. Suzuki, Takefumi; Kim, Yoon Nam; Yuasa, Hiroko;Yamada, Toshiro. Jpn. Kokai Tokkyo Koho (2001), JP 2001247494 A20010911. Sekiya, Akira; Ko, Masataka; Tamura, Masanori; Yamada,Toshiro. Jpn. Kokai Tokkyo Koho (2001), JP 2001240567 A 20010904. Kim,Yoon Nam; Yuasa, Hiroko; Suzuki, Takefumi; Yamada, Toshiro. Jpn. KokaiTokkyo Koho (2001), JP 2001240569 A 20010904. Sakyu, Fuyuhiko; Takada,Naokado; Komata, Takeo; Kim, Yoon Nam; Yamada, Toshiro; Sugimoto,Tatsuya. Jpn. Kokai Tokkyo Koho (2000), JP 2000247912 A 20000912. Saku,Fuyuhiko; Takada, Naokado; Inomura, Hideaki; Komata, Takeo. Jpn. KokaiTokkyo Koho (2000), JP 2000226346 A 20000815. Yamada, Toshiro; Sugimoto,Tatsuya; Sugawara, Mitsuru. PCT Int. Appl. (1999), WO 9950209 A119991007. Yamada, Toshiro; Uruma, Takashi; Sugimoto, Tatsuya. PCT Int.Appl. (1999), WO 9933771 A1 19990708. Sekiya, Akira; Yamada, Toshirou;Uruma, Takashi; Sugimoto, Tatsuya. PCT Int. Appl. (1998), WO 9851650 A119981119. Banks, Ronald E.; Barlow, Michael G.; Haszeldine, Robert N.;Lappin, M.; Matthews, V.; Tucker, N. I. Journal of the Chemical Society[Section] C: Organic (1968), (5), 548-50. 199989-36-1 Cyclopentane,1,1,2,2,3,4- hexafluoro- 123768-18-3 Cyclopentane, 1,1,2,2,3,3-Stepanov, A. A.; Delyagina, N. I.; Cherstkov, V. F. Russian Journal ofhexafluoro- Organic Chemistry (2010), 46(9), 1290-1295. Saku, Fuyuhiko;Takada, Naokado; Inomura, Hideaki; Komata, Takeo. Jpn. Kokai Tokkyo Koho(2000), JP 2000226346 A 20000815. Sekiya, Akira; Yamada, Toshirou;Uruma, Takashi; Sugimoto, Tatsuya. PCT Int. Appl. (1998), WO 9851650 A119981119. Sekiya, Akira; Yamada, Toshiro; Watanabe, Kazunori. Jpn. KokaiTokkyo Koho (1996), JP 08143487 A 19960604. Yamada, Toshiro; Mitsuda,Yasuhiro. PCT Int. Appl. (1994), WO 9407829 A1 19940414. Anton, DouglasRobert. PCT Int. Appl. (1991), WO 9113846 A1 19910919. Bielefeldt,Dietmar; Braden, Rudolf; Negele, Michael; Ziemann, Heinz. Eur. Pat.Appl. (1991), EP 442087 A1 19910821. Bielefeldt, Dietmar; Marhold,Albrecht; Negele, Michael. Ger. Offen. (1989), DE 3735467 A1 19890503.1259529-57-1 Cyclopentane, 1,1,2,2,3- pentafluoro- CYCLOHEXANES 830-15-9Cyclohexane, Evans, D. E. M.; Feast, W. J.; Stephens, R.; Tatlow, J. C.Journal of the 1,1,2,2,3,3,4,4-octafluoro- Chemical Society (1963),(October), 4828-34. FURANS 634191-25-6 Furan, 2,3,4,4-tetrafluorotetrahydro-2,3- bis(trifluoromethyl)- 377-83-3 Furan,2,2,3,3,4,4,5- Chepik, S. D.; Cherstkov, V. F.; Mysov, E. I.; Aerov, AF.; Galakhov, M. heptafluorotetrahydro-5- V.; Sterlin, S. R.; German, L.S. Izvestiya Akademii Nauk SSSR, Seriya (trifluoromethyl)-Khimicheskaya(1991), (11), 2611-18. Abe, Takashi; Nagase, Shunji.Journal of Fluorine Chemistry (1979), 13(6), 519-30. Abe, Takashi;Nagase, Shunji. Jpn. Kokai Tokkyo Koho (1978), JP 53025552 A 19780309.Abe, Takashi; Nagase, Toshiharu; Baba, Hajime. Jpn. Tokkyo Koho (1976),JP 51045594 B 19761204. Abe, Takashi; Nagase, Shunji; Baba, Hajime. Jpn.Kokai Tokkyo Koho (1976), JP 51082257 A 19760719. Abe, Takashi; Nagase,Shunji; Baba, Hajime. Jpn. Kokai Tokkyo Koho (1975), JP 50106955 A19750822. Abe, Takashi; Nagase, Toshiharu; Baba, Hajime. Jpn. TokkyoKoho (1973), JP 48012742 B 19730423. 374-53-8 Furan, 2,2,3,3,4,5,5- Jpn.Kokai Tokkyo Koho (1981), JP 56142877 A 19811107.heptafluorotetrahydro-4- (trifluoromethyl)- Abe, Takashi; Nagase,Shunji. Journal of Fluorine Chemistry (1979), 13(6), 519-30. Abe,Takashi; Nagase, Shunji. Jpn. Kokai Tokkyo Koho (1978), JP 53124259 A19781030. Abe, Takashi; Nagase, Shunji. Jpn. Kokai Tokkyo Koho (1978),JP 53025552 A 19780309. Abe, Takashi; Nagase, Toshiharu; Baba, Hajime.Jpn. Tokkyo Koho (1976), JP 51045594 B 19761204. Abe, Takashi; Nagase,Shunji; Baba, Hajime. Jpn. Kokai Tokkyo Koho (1976), JP 51082257 A19760719. 133618-52-7 Furan, 2,2,3,4,5- pentafluorotetrahydro-5-(trifluoromethyl)-, (2a,3a,4β)- 133618-53-8 Furan, 2,2,3,4,5- Burdon,James; Coe, Paul L; Smith, J. Anthony; Tatlow, John Colin.pentafluorotetrahydro-5- Journal of Fluorine Chemistry (1991), 51(2),179-96. (trifluoromethyl)-, (2α,3β,4α)- (9Cl) 133618-52-7 Furan,2,2,3,4,5- Burdon, James; Coe, Paul L.; Smith, J. Anthony; Tatlow, JohnColin. pentafluorotetrahydro-5- Journal of Fluorine Chemistry (1991),51(2), 179-96. (trifluoromethyl)-, (2α,3α,4β)- (9Cl) 61340-70-3 Furan,2,2,3,3,5,5- Abe, Takashi; Nagase, Shunji; Baba, Hajime. Bulletin of theChemical hexafluorotetrahydro-4- Society of Japan (1976), 49(7),1888-92. (trifluoromethyl)- 634191-26-7 Furan, 2,3-difluorotetrahydro-2,3- bis(trifluoromethyl)- 1026470-51-8 Furan,2-chloro- 2,3,3,4,4,5,5- heptafluorotetrahydro- 179017-83-5 Furan,2,2,3,3,4,4,5- heptafluorotetrahydro-5- methyl- 133618-59-4 Furan,2,2,3,3,4,5- Burdon, James; Coe, Paul L.; Smith, J. Anthony; Tatlow,John Colin. hexafluorotetrahydro-5- Journal of Fluorine Chemistry(1991), 51(2), 179-96. (trifluoromethyl)-, trans- (9Cl) 133618-49-2Furan, 2,2,3,3,4,5- Burdon, James; Coe, Paul L.; Smith, J. Anthony;Tatlow, John Colin. hexafluorotetrahydro-5- Journal of FluorineChemistry (1991), 51(2), 179-96. (trifluoromethyl)-, cis- (9Cl) PYRANS71546-79-7 2H-Pyran, 2,2,3,3,4,5,5,6,6- Abe, Takashi; Nagase, Shunji.Journal of Fluorine Chemistry (1979), nonafluorotetrahydro-4- 13(6),519-30. 356-47-8 2H-Pyran, 2,2,3,3,4,4,5,5,6- Abe, Takashi; Tamura,Masanori; Sekiya, Akira. Journal of Fluorine nonafluorotetrahydro-6-Chemistry (2005), 126(3), 325-332. (trifluoromethyl)- Jpn. Kokai TokkyoKoho (1980), JP 55051084 A 19800414. Abe, Takashi; Nagase, Shunji.Journal of Fluorine Chemistry (1979), 13(6), 519-30. Abe, Takashi;Kodaira, Kazuo; Baba, Hajime; Nagase, Shunji. Journal of FluorineChemistry (1978), 12(1), 1-25. No Inventor data available. (1961), GB862538 19610315. Sander, Manfred; Helfrich, Frledrich; Blochl, Walter.(1959), DE 1069639 19591126. No Inventor data available. (1954), GB718318 19541110. 61340-74-7 2H-Pyran, 2,2,3,3,4,4,5,6,6- Abe, Takashi;Nagase, Shunji. Journal of Fluorine Chemistry (1979),nonafluorotetrahydro-5- 13(6), 519-30. (trifluoromethyl)- Abe, Takashi;Nagase, Shunji; Baba, Hajime. Bulletin of the Chemical Society of Japan(1976), 49(7), 1888-92. Abe, Takashi; Kodaira, Kazuo; Baba, Hajime;Nagase, Shunji. Journal of Fluorine Chemistry (1978), 12(1), 1-25.657-48-7 2H-Pyran, 2,2,6,6- Wang, Chia-Lin J. Organic Reactions(Hoboken, NJ, United States) tetrafluorotetrahydro-4- (1985), 34, No pp.given. (trifluoromethyl)- Dmowski, Wojciech; Kolinski, Ryszard A. PolishJournal of Chemistry (1978), 52(1), 71-85. Hasek, W. R.; Smith, W. C.;Engelhardt, V. A. Journal of the American Chemical Society (1960), 82,543-51. 874634-55-6 2H-Pyran, 2,2,3,3,4,4,5,5,6- Abe, Takashi; Tamura,Masanori; Sekiya, Akira. Journal of Fluorine nonafluorotetrahydro-6-Chemistry (2005), 126(3), 325-332. methyl- 355-79-3Perfluorotetrahydropyran Wang, Chia-Lin J. Organic Reactions (Hoboken,NJ, United States) (1985), 34, No pp. given. Abe, Takashi; Tamura,Masanori; Sekiya, Akira. Journal of Fluorine Chemistry (2005), 126(3),325-332. Moldavsky, Dmitrii D.; Furin, Georgii G. Journal of FluorineChemistry (1998), 87(1), 111-121. Nishimura, Masakatsu; Shibuya,Masashi; Okada, Naoya; Tokunaga, Shinji. Jpn. Kokai Tokkyo Koho (1989),JP 01249728 A 19891005. Nishimura, Masakatsu; Okada, Naoya; Murata,Yasuo; Hirai, Yasuhiko. Eur. Pat. Appl. (1988), EP 271272 A2 19880615.Abe, Takashi; Nagase, Shunji. Journal of Fluorine Chemistry (1979),13(6), 519-30. De Pasquale, Ralph J. Journal of Organic Chemistry(1973), 38(17), 3025-30. Abe, Takashi; Nagase, Toshiharu; Baba, Hajime.Jpn. Tokkyo Koho (1973), JP 48012742 B 19730423. Henne, Albert L;Richter, Sidney B. Journal of the American Chemical Society (1952), 74,5420-2. Kauck, Edward A.; Simons, Joseph H. (1952), U.S. Pat. No.2,594,272 19520429. 362631-93-4 2H-Pyran, 2,2,3,3,4,5,5,6-octafluorotetrahydro-, (4R,6S)-rel- 65601-69-62H-Pyran,2,2,3,3,4,4,5,5,6- Zapevalova, T. B.; Plashkin, V. S.;Selishchev, B. N.; Bil’dinov, K. N.; nonafluorotetrahydro- Shcherbakova,M. S. Zhurnal Organicheskoi Khimii (1977), 13(12), 2573-4.

General schemes for the synthesis of halogenated compounds, includingthe anesthesia compounds are provided, e.g., in Chambers, “Fluorine inOrganic Chemistry.” WileyBlackwell, 2004. ISBN:978-1405107877; Iskra,“Halogenated Heterocycles: Synthesis, Application and Environment(Topics in Heterocyclic Chemistry).” Springer, 2012.ISBN:978-3642251023; and Gakh, and Kirk, “Fluorinated Heterocycles” (ACSSymposium Series). American Chemical Society, 2009. ISBN:978-0841269538.

Halogenated Alcohols

Synthesis schemes for halogenated alcohols are summarized in Table 4 andcan be applied to the synthesis of the halogenated alcohol anestheticcompounds described herein, including those of Formula I. Illustrativereferences describing synthesis of halogenated alcohols include withoutlimitation, e.g., Mochalina, et al., Akademii Nauk SSSR (1966), 169(6),1346-9; Delyagina, et al., Akademii Nauk SSSR, Seriya Khimicheskaya(1972), (2), 376-80; Venturini, et al., Chimica Oggi (2008), 26(4),36-38; Navarrini, et al., Journal of Fluorine Chemistry (2008), 129(8),680-685; Adcock, et al., Journal of Fluorine Chemistry (1987), 37(3),327-36; Cantini, et al., Ital. Appl. (2007), IT 2007MI1481 A1 20071023;Marraccini, et al., Eur. Pat. Appl. (1990), EP 404076 A1; Adcock, etal., Journal of Organic Chemistry (1973), 38(20), 3617-18; Aldrich, etal., Journal of Organic Chemistry (1964), 29(1), 11-15; Weis, et al.,Industrial & Engineering Chemistry Research (2005), 44(23), 8883-8891;Arimura, et al., Journal of Chemical Research, Synopses (1994), (5),202-3; Du, et al., Journal of the American Chemical Society (1990),112(5), 1920-6; Galimberti, et al., Journal of Fluorine Chemistry(2005), 126(11-12), 1578-1586; and Navarrini, et al., Eur. Pat. Appl.(2004), EP 1462434 A1. Generally, fluorinated alcohols can besynthesized using techniques of direct hypofluorite addition and reversehypofluorite addition, described, e.g., in Navarrini, et al., Journal ofFluorine Chemistry (2008), 129(8), 680-685.

In a typical direct hypofluorite addition, a stream of hypofluorite isbubbled into a solution of an olefin maintained at the desiredtemperature in a semi-batch method in order to operate in excess ofolefin. The addition reactor can be standard dimensions designed 250 mlAmerican Iron and Steel Institute (AISI) 316 stainless steel cooled byan external vessel. The reactor can be realized with a discharge bottomvalve and two feeding tubes. The reactor's head can be equipped with: anoutgoing tube for collecting the off-gas stream and amechanical/magnetic transmission stirring system. The feed of theaddition reactor and the off-gases can be analysed on-line, e.g., viainfrared (IR), gas chromatography-thermal conductivity detector (GC-TCD)and gas chromatography-infrared (GC-IR). At the end of the addition, thereactor can be stripped with 4 nL/h of helium for about 30 min, thevessel is unloaded and the resulting mixture analysed, e.g., via gaschromatography (GC), GC- mass spectrometry (MS) e nuclear magneticresonance (NMR) ¹⁹F. The raw reaction mixture can be distilled in vacuumor at atmospheric pressure.

In a typical reverse hypofluorite addition, a stream of olefin isbubbled into a solution of hypofluorite in order to operate in excess ofhypofluorite at the desired temperature. The reaction can be carried outin a continuous stirred-tank reactor (CSTR) with a continuous feed ofboth the reagents. The reactor is charged with the solvent, cooled atthe desired temperature and a gaseous stream comprising CF₃OF (2.35nL/h), He (2.5 nL/h), COF₂ (0.3 nL/h) is fed in the reactor (e.g., forabout 12 min) before starting to add the olefin. After adding theolefin, for safety reasons it is compulsory to eliminate the residualhypofluorite before opening the reactor. In order to remove the majorityof the overloaded hypofluorite from the bulk, the liquid phase can bestripped with a stream of 4 nL/h of helium for about 30 min at thetemperature between −80 and −90° C., after that maintaining thetemperature in the range −80 to −90° C. about 2 ml of CFCl═CFCl can beadded in the reactor to eliminate the remaining traces of hypofluorite.The traces of CF₃OF react completely with CFCl═CFCl producingCF₃O—CFCl—CF₂Cl.

Halogenated Cyclopentanes and Cyclohexanes

Synthesis schemes for halogenated cyclopentanes and cyclohexanes aresummarized in Table 4 and can be applied to the synthesis of thehalogenated cyclopentane and cyclohexane anesthetic compounds describedherein, including those of Formulae V and VI. Illustrative referencesdescribing synthesis of halogenated cyclopentanes and halogenatedcyclohexanes include without limitation, e.g., Imura, et al., Jpn. KokaiTokkyo Koho (2001), JP 2001261594A; Heitzman, et al., Journal of theChemical Society (1963), 281-9; Sekiya, Akira; et al., PCT Int. Publ. WO96/00707 A1, Sekiya, et al., Jpn. Kokai Tokkyo Koho (1996), JP 08143487A; Rao, et al, PCT Int. Publ. WO 93/05002 A2; Burdon, et al., Journal ofthe Chemical Society (1965), (April), 2382-91; Yamada, et al., Jpn.Kokai Tokkyo Koho (1999), JP 11292807 A; Otsuki, Petrotech (Tokyo,Japan) (2005), 28(7), 489-493; Takada, et al., Jpn. Kokai Tokkyo Koho2002), JP 2002241325 A; Suzuki, et al., Jpn. Kokai Tokkyo Koho (2001),JP 2001247494 A; Sekiya, et al., Jpn. Kokai Tokkyo Koho (2001), JP2001240567 A; Kim, et al., Jpn. Kokai Tokkyo Koho (2001), JP 2001240569A; Sakyu, et al., Jpn. Kokai Tokkyo Koho (2000), JP 2000247912 A; Saku,et al, Jpn. Kokai Tokkyo Koho (2000), JP 2000226346 A; Yamada, et al.,PCT Int. Publ. WO 99/50209 A1; Yamada, et al., PCT Int. Publ. WO99/33771 A1; Sekiya, et al., PCT Int. Publ. WO 98/51650 A1; Banks, etal., Journal of the Chemical Society [Section] C: Organic (1968),(5):548-50; Stepanov, et al., Russian Journal of Organic Chemistry(2010), 46(9):1290-1295; Saku, et al., Jpn. Kokai Tokkyo Koho (2000), JP2000226346 A; Sekiya, et al., PCT Int. Publ. WO 98/51650 A1; Sekya, etal., Jpn. Kokai Tokkyo Koho (1996), JP 08143487 A; Yamada, et al., PCTInt. Publ. WO 94/07829 A1; Anton, PCT Int. Publ. WO 91/13846 A1;Bielefeldt, et al., Eur. Pat. Appl. (1991), EP 442087 A1; Bielefeldt, etal., Ger. Offen. (1989), DE 3735467 A1; and Evans, et al., Journal ofthe Chemical Society (1963), (October), 4828-34. Generally, fluorinatedcyclopentanes and fluorinated cyclohexanes can be synthesized usingtechniques described, e.g., in Evans, et al., Journal of the ChemicalSociety (1963), (October), 4828-34; Burdon, et al., Journal of theChemical Society (1965), (April), 2382-91.

A halogenated cyclopentane or halogenated cyclohexane can be synthesizedby reduction of a halogenated cycloalkene with lithium aluminum hydride,as described, for example, by Evans, et al., Journal of the ChemicalSociety (1963), (October), 4828-34. In this approach, a(poly)fluorocycloalkene is mixed with lithium aluminum hydride in ether,producing several species of (poly)fluorocycloalkenes in anaddition-elimination process. These (poly)fluorocycloalkenes can becharacterized and several (poly)fluorocycloalkanes and related compoundscan be made from them. Elimination is the most important reaction ofsuch systems, and a possible pathway for a cis-E2-process. For reactionof the polyfluorocycloalkene with lithium aluminum anhydride, the(poly)fluorocycloalkene is added dropwise to a stirred suspension oflithium aluminum hydride in diethyl ether at −20° C. When the initialreaction subsides, the solution is refluxed, then cooled to −20° C. and50% v/v sulphuric acid is added dropwise, followed by water until noprecipitate remained. The dried (MgSO₄) ethereal solution is evaporatedthrough a vacuum jacketed column (1′×1½″) packed with glass helices toleave a mixture of (poly)fluorocycloalkenes (180 g.) which is separatedby preparative gas chromatography (column type B, 100° C., N₂ flow-rate601./hr.). 1H-Nonafluorocyclohexene prepared in this way contained atrace of ether which can be removed by a second gas-chromatographicseparation in a column of type A packed with tritolylphosphate-kieselguhr (1:3). The double bond of the(poly)fluorocycloalkenes can be readily saturated, e.g., by fluorinationwith cobaltic fluoride, or by catalytic hydrogenation at atmosphericpressure to produce the corresponding desired (poly)fluorocycloalkane.Characterization of the (poly)fluorocycloalkenes(poly)fluorocycloalkanes can be performed using standard methodologies,including, e.g., oxidation, NMR spectroscopy, mass spectroscopy,resistance to alkali, and gas chromatography.

The vapour-phase fluorination of a cycloalkadiene with cobaltic fluorideto produce the corresponding (poly)fluorocycloalkane and the alternativesynthesis of the (poly)fluorocycloalkane starting from a(poly)fluorocycloalkene, fluorinating with cobaltic fluoride and thenreducing with lithium aluminum hydride are described, for example, byHeitzman, et al., Journal of the Chemical Society (1963), 281-9. Forvapour-phase fluorination of a cycloalkadiene, the cycloalkadiene is fedinto a reactor containing cobalt trifluoride maintained at 190° C.-250°C. The products are collected in a copper trap cooled by solid carbondioxide and any remaining in the reactor is swept into the trap by agentle stream of nitrogen. The total product is poured into ice-waterand washed with sodium hydrogen carbonate solution. The clear organiclayer is separated, and a resin discarded. The combined products aredistilled through a vacuum-jacketed column (4′×1″) packed with Dixongauze rings ( 1/16″× 1/16″). The distillation is controlled byanalytical gas chromatography. For synthesis of the(poly)fluorocycloalkanes the corresponding (poly)fluorocycloalkenes, the(poly)fluorocycloalkene is first chlorinated and then reduced. Forchlorination, the olefin and liquid chlorine are irradiated withultraviolet light for 4 hr. in a quartz flask fitted with a condenser at−78° C. The excess of chlorine is removed by washing the products withaqueous sodium hydrogen carbonate (10% w/v). The(poly)chlorofluorocycloalkane product is dried (P205) and distilled, andcan be analyzed by gas chromatography and infrared spectroscopy. Forreduction, the (poly)chlorofluorocycloalkane product in dry ether isadded to a stirred suspension of lithium aluminum hydride in dry etherat 0° C. The apparatus is fitted with a condenser cooled to −78° C.After 5 hours' stirring at 15° C., unchanged lithium aluminum hydride isdestroyed at 0° C. by the careful addition of water followed byhydrochloric acid (10% v/v) to dissolve the solid. The ethereal layer isdistilled through a column (2′×¼″) and the residue can be analyzed bygas chromatography and infrared spectroscopy.

The synthesis of (poly)fluorocycloalkanes by addition of chlorine to thecorresponding (poly)fluorocycloalkene, followed by lithium aluminumhydride reduction is described, for example, by Burdon, et al., Journalof the Chemical Society (1965), (April), 2382-91. For chlorination, the(poly)fluorocycloalkene is mixed with an excess of chlorine in thepresence of ultraviolet irradiation. For reduction, the(poly)chlorofluorocycloalkane in dry ether are added over 2 hr. to astirred solution of lithium aluminum hydride in dry ether at 0° C. Thereaction mixture is stirred for a further 2 hr., and then the excess oflithium aluminum hydride is destroyed in the usual way with 50%sulphuric acid. Distillation of the dried (MgSO₄) ether layer through a6 in. column packed with glass helices leaves a residue. The species inthe residue can be separated by gas chromatography on a preparativescale [e.g., column 4.8 m.×35 mm. diam., packed with dinonylphthalate-kieselguhr (1:2); temp. 98° C. N₂, flow-rate 11 l./hr.]. Theeluted components can be analyzed by infrared spectroscopy (IR) and/orNMR.

Halogenated Dioxanes

Synthesis schemes for halogenated dioxanes are summarized in Table 4 andcan be applied to the synthesis of the halogenated dioxane anestheticcompounds described herein, including those of Formula III. Illustrativereferences describing synthesis of halogenated dioxanes include withoutlimitation, e.g., Krespan, et al., PCT Int. Appl. (1991), WO 91/04251;Krespan, et al., Journal of Organic Chemistry (1991), 56(12), 3915-23;Coe, et al., Journal of Fluorine Chemistry (1975), 6(2), 115-28; Burdon,et al., U.S. Pat. No. 3,883,559; Burdon, et al., Tetrahedron (1971),27(19), 4533-51; Adcock, et al., Journal of Fluorine Chemistry (1980),16(3), 297-300; Dodman, et al., Journal of Fluorine Chemistry (1976),8(3), 263-74; Meinert, et al., Journal of Fluorine Chemistry (1992),59(3), 351-65; Berenblit, et al., Zhurnal Prikladnoi Khimii(Sankt-Peterburg, Russian Federation) (1980), 53(4), 858-61; Lagow, etal., U.S. Pat. No. 4,113,435; Berenblit, et al., Zhurnal PrikladnoiKhimii (Sankt-Peterburg, Russian Federation) (1975), 48(10), 2206-10;Adcock, et al., Journal of Organic Chemistry (1975), 40(22), 3271-5;Abe, et al., Jpn. Tokkyo Koho (1974), JP 49027588B; Berenblit, et al.Zhurnal Organicheskoi Khimii (1974), 10(10), 2031-5; Adcock, et al.,Journal of the American Chemical Society (1974), 96(24), 7588; Abe, etal., Bulletin of the Chemical Society of Japan (1973), 46(8), 2524-7;and Sianesi, et al., Ger. Offen. (1972), DE 2111696A. Generally,fluorinated dioxanes can be synthesized by fluorinating dioxanes overcobalt trifluoride (CoF₃) or over potassium tetrafluorocobaltate, forexample, as described in Burdon, et al., Tetrahedron (1971), 27(19),4533-51. Polyfluorodioxenes generally can be synthesized bydehydrofluorination of the appropriate polyfluorodioxane, for example,as described in Coe, et al., Journal of Fluorine Chemistry (1975), 6(2),115-28.

In a typical fluorination of dioxane over CoF₃, as described, e.g., byBurdon, et al., Tetrahedron (1971), 27(19), 4533-51, dioxane is passedinto a stirred bed of CoF₃ (apparatus has been described in Bohme, Br.Dtsch. Chem. Ges. 74:248 (1941) and Bordwell, et al., J Amer Chem Soc79:376 (1957) at 100° C. in a stream of N₂ (10 dm³/hr). After all thedioxane enters the reactor (about 3 hrs), the N₂ stream is continued fora further 2 hr. The products are trapped at −78° C. and poured into icedwater. Separation gives a pale yellow liquid which deposits crystals ofa tetrafluorodioxane on being stored at −60° C. The products frommultiple (e.g., four) such fluorinations are washed with aqueous NaHCO₃and distilled from P₂O₅ up a 2′ vacuum jacketed glass column packed withDixon gauze rings ( 1/16″× 1/16″). The fractions collected can befurther separated, e.g., by analytical gas-liquid chromatography (GLC)and analyzed, e.g., by GLC, IR, MS and/or NMR.

In a typical fluorination of dioxane over KCoF₄, as described, e.g., byBurdon, et al., Tetrahedron (1971), 27(19), 4533-51, dioxane is passedin a stream of N₂ (10 dm³/hr) over a heated (230° C.) and stirred bed ofKCoF₄ (the apparatus has been described in Burdon, et al., J. Chem Soc.2585 (1969)). The addition takes about 3 hr., and the N₂ stream iscontinued for 2 hr. afterwards. The products are collected in a coppertrap cooled to −78° C.; washed with water and dried to give crudematerial. The crude product, or a sample thereof, can be furtherseparated, e.g., by analytical gas-liquid chromatography (GLC) andanalyzed, e.g., by GLC, IR, MS and/or NMR.

In a typical isomerization of the polyfluorodioxanes over AlF₃, asdescribed, e.g., by Burdon, et al., Tetrahedron (1971), 27(19), 4533-51,dioxane is passed in a stream of N₂ (1.5 dm³/hr) through a heated (tempstated in each case) glass tube (12″×¾″) packed with AlF₃, powdersupported on glass chips. The products are collected in a trap cooled inliquid air. The polyfluorodioxans are isomerized at elevatedtemperatures in the range of about 390° C. to about 490° C. Theisomerized products can be further separated, e.g., by analyticalgas-liquid chromatography (GLC) and analyzed, e.g., by GLC, IR and/orNMR.

Halogenated Dioxolanes

Synthesis schemes for halogenated dioxolanes are summarized in Table 4and can be applied to the synthesis of the halogenated dioxolaneanesthetic compounds described herein, including those of Formula IV.Illustrative references describing synthesis of halogenated dioxolanesinclude without limitation, e.g., Kawa, et al., Jpn. Kokai Tokkyo Koho(2000), JP 2000143657A; Russo, et al., Eur. Pat. Appl. (1999), EP 937720A1; Russo, et al., Journal of Fluorine Chemistry (2004), 125(1), 73-78;Navarrini, et al., Journal of Fluorine Chemistry (1995), 71(1), 111-17;Navarrini, et al., Eur. Pat. Appl. (1992), EP 499158A; Navarrini, etal., Eur. Pat. Appl. (1995), EP 683181 A1; Muffler, et al., Journal ofFluorine Chemistry (1982), 21(2), 107-32; Anton, et al., PCT Int. Appl.(1991), WO 9109025 A2; Berenblit, et al., Zhurnal Organicheskoi Khimii(1974), 10(10), 2031-5; Berenblit, et al., Zhurnal Prikladnoi Khimii(Sankt-Peterburg, Russian Federation) (1975), 48(10), 2206-10; Prager,Journal of Organic Chemistry (1966), 31(2), 392-4; Throckmorton, Journalof Organic Chemistry (1969), 34(11), 3438-40; Sianesi, et al., Ger.Offen. (1972), DE 2111696 A; and Navarrini, et al., Eur. Pat. Appl.(1991), EP460948A2. Generally, fluorinated dioxolanes can be synthesizedby addition of bis-(fluoroxy)difluoromethane (BDM) to halogenatedalkenes, e.g., as described by Navarrini, et al., J Fluorine Chem71:111-117 (1995) or by reaction of chloroalkoxyfluorocarbonyl halidesor ketones with fluoride ions, e.g., as described by Muffler, et al., JFluorine Chem 21:107-132 (1982).

In a typical reaction for addition of bis-(fluoroxy)difluoromethane(BDM) to halogenated alkenes, e.g., as described by Navarrini, et al., JFluorine Chem 71:111-117 (1995), a semi-continuous or continuous systemcan be used. In a general procedure for a semi-continuous system, aglass reactor equipped with a mechanical stirrer, reflux condenser,thermocouple, inner plunging pipes, maintained at temperatures in therange of about −196° C. to 25° C. (see, Table 1 of Navarrini, et al.,supra) is charged with a 0.2-5 M solution (50-300 ml) of the olefin inCFCl₃, CF₂Cl₂ or with the pure olefin. A flow ofbis(fluoroxy)difluoromethane (usually about 1 liter per hour flow rate)diluted with He in a 1:5 ratio is then fed into the reactor until 90% ofthe olefin is converted. At the end of the addition, helium is bubbledthrough the reaction mixture to remove traces of unreacted CF₂(OF)₂. Thedioxolanes are isolated via fractional distillation using an HMS 500 CSpaltrohr Fischer apparatus. In a general procedure for a continuoussystem, bis(fluoroxy)difluoromethane at a flow rate of about 0.4 litersper hour diluted with He (about 2 liters per hour) and the olefin (36mmol per hour) are simultaneously but separately fed, at thetemperatures in the range of about −196° C. to 25° C. (see, Table 1 ofNavarrini, et al., supra), into a multi-neck glass reactor containing a10⁻¹ to 10⁻²M solution of the olefin and equipped with a magneticentrainment mechanical stirrer, reflux cooler, thermocouple and innerplunging pipes. After feeding the reagents for 4 hr, helium is bubbledthrough the reaction mixture to remove traces of unreacted CF₂(OF)₂. Thereaction mixture can be purified by fractional distillation. Thereaction products can be separated through traps cooled to −50° C., −80°C., −100° C., −120° C. and −196° C., as appropriate. Furtherdistillation of the mixtures collected at −100° C. to −120° C. throughtraps cooled to −50° C., −60° C., −75° C., −100° C., −105° C., −112° C.,−120° C. and −196° C., respectively, allows collection of the puredioxolane, e.g., in the −75° C., −100° C., −112° C. traps. The collecteddioxolane product can be analyzed, e.g., by GLC, IR, MS and/or NMR.

Halogenated Pyrans

Synthesis schemes for halogenated pyrans are summarized in Table 4 andcan be applied to the synthesis of the halogenated tetrahydropyrananesthetic compounds described herein, including those of Formula VII.Illustrative references describing synthesis of halogenated pyransinclude without limitation, e.g., Abe, et al., Journal of FluorineChemistry (1979), 13(6), 519-30; Abe, et al., Journal of FluorineChemistry (2005), 126(3), 325-332; Jpn. Kokai Tokkyo Koho (1980), JP55051084 A; Abe, et al., Journal of Fluorine Chemistry (1979), 13(6),519-30; Abe, et al., Journal of Fluorine Chemistry (1978), 12(1), 1-25;GB Pat. No. 862538; Sander, et al., (1959), DE 1069639; GB Pat No.718318; Abe, et al., Journal of Fluorine Chemistry (1979), 13(6),519-30; Abe, et al., Bulletin of the Chemical Society of Japan (1976),49(7), 1888-92; Wang, Organic Reactions (Hoboken, N.J., United States)(1985), vol. 34; Dmowski, et al., Polish Journal of Chemistry (1978),52(1), 71-85; Hasek, et al., Journal of the American Chemical Society(1960), 82, 543-51; Abe, et al., Journal of Fluorine Chemistry (2005),126(3), 325-332; Moldaysky, et al., Journal of Fluorine Chemistry(1998), 87(1), 111-121; Nishimura, et al., Jpn. Kokai Tokkyo Koho(1989), JP 01249728 A; Nishimura, Eur. Pat. Appl. (1988), EP 271272 A2;Abe, et al., Journal of Fluorine Chemistry (1979), 13(6), 519-30; DePasquale, Journal of Organic Chemistry (1973), 38(17), 3025-30; Abe, etal., Jpn. Tokkyo Koho (1973), JP 48012742 B; Henne, et al., Journal ofthe American Chemical Society (1952), 74, 5420-2; Kauck, et al., (1952),U.S. Pat. No. 2,594,272; and Zapevalova, et al., Zhurnal OrganicheskoiKhimii (1977), 13(12), 2573-4. Generally, fluorinated pyrans can besynthesized by reducing to a diol a perfluorinated dibasic ester,cyclizing the diol to an ether, chlorinating the cyclic ether to producea perhalogenated cyclic ether, and then fluorinating the perhalogenatedcyclic ether to produce the desired perfluorinated cyclic ether.Typically, for reduction of a perfluorinated dibasic ester to a diol,the perfluorinated dibasic ester is reduced with LiAlH₄ in dry ether togive the diol. The diol can be recrystallized, e.g., from benzene. Forcyclization, a mixture of the glycol and concentrated sulfuric acid (10g. or 0.1 mole) is kept in an oil bath at a temperature in the range ofabout 185° C. to about 250° C. The cyclic ether which distilled over canbe dried, e.g., with Drierite, and redistilled. For chlorination of thecyclic ether, the cyclic ether is placed in a quartz flask illuminatedwith a sun lamp or UV lamp. Chlorine is bubbled through for two days. Anice-cooled trap attached to the reflux condenser caught entrainedmaterial, which is returned from time to time. For fluorination of thecyclic ether to produce the perfluorinated cyclic ether, the cyclicether and SbF₃Cl₂ are heated at 155° C. for 24 hours in a steel bomb.The pressure rises to about 230 p.s.i. and drops to about 50 p.s.i. oncooling to room temperature. This pressure is released into a Dry Icetrap which collects raw perfluorinated cyclic ether. For larger rings, atwo-step procedure may be applied. The cyclic ether and SbF₃Cl₂ areheated to 125° C. for seven hours in a 450 ml. steel bomb, with shaking.The pressure rises to about 75 p.s.i. The temperature is raised to 160°C. for 16 hours, which raises pressure to 280 p.s.i. After cooling, alight fraction is collected by distillation. The light fraction andSbF₃Cl₂ are shaken at 160° C. for five hours in a bomb. The pressurerises to about 320 p.s.i. After cooling, repeated distillation of thecrude product gives the desired perfluorinated cyclic ether. Thisperfluorinated cyclic ether can be purified by passage through two 10%HCl bubblers to remove traces of antimony salts, concentrated H₂SO₄ toremove unsaturated impurities and finally distilled from P₂O₅. Thepurified material can be analyzed, e.g., by GLC, IR, MS and/or NMR.

Halogenated Furans

Synthesis schemes for halogenated furans are summarized in Table 4 andcan be applied to the synthesis of the halogenated tetrahydrofurananesthetic compounds described herein, including those of Formula VI.Illustrative references describing synthesis of halogenated furansinclude without limitation, e.g., Chepik, et al., Izvestiya AkademiiNauk SSSR, Seriya Khimicheskaya (1991), (11), 2611-18; Abe, et al.,Journal of Fluorine Chemistry (1979), 13(6), 519-30; Abe, et al., Jpn.Kokai Tokkyo Koho (1978), JP53025552A; Abe, et al., Jpn. Tokkyo Koho(1976), JP 51045594 B; Abe, et al., Jpn. Kokai Tokkyo Koho (1976), JP51082257 A; Abe, et al., Jpn. Kokai Tokkyo Koho (1975), JP 50106955 A;Abe, et al., Jpn. Tokkyo Koho (1973), JP 48012742 B; Jpn. Kokai TokkyoKoho (1981), JP 56142877 A.; Abe, et al., Journal of Fluorine Chemistry(1979), 13(6), 519-30; Abe, et al., Jpn. Kokai Tokkyo Koho (1978), JP53124259 A; Burdon, et al., Journal of Fluorine Chemistry (1991), 51(2),179-96; and Abe, et al., Bulletin of the Chemical Society of Japan(1976), 49(7), 1888-92. Generally, fluorinated furans can be produced,e.g., by electrochemical fluorination or by exposure of atetrahydrofuran to tetrafluorocobaltate(III) and/or cobalt trifluoride.

A typical electrochemical fluorination reaction is described, e.g., byAbe and Nagase, J Fluorine Chem 13:519-530 (1979). An electrolytic cellthat can be used is described in Abe, et al., J Fluorine Chem 12:1(1978); and Abe, et al., J Fluorine Chem 12:359 (1976). The compound(e.g., furan) to be fluorinated is charged into the cell which contained1 liter electrochemically purified anhydrous hydrogen fluoride, and theresulting solution is subjected to fluorination with an anodic currentdensity of 3.5 A/dm², a cell voltage of 5.0˜6.2 V, and a celltemperature of about 5-6° C. over a period of 437 min (234 Ahr) untilthe cell voltage rose rapidly up to 9.0 V. Initially, the productscollected in cold traps (−196° C.) are roughly separated into at leasttwo fractions using the traps of a low-temperature distillation unit.After that, the composition of products in these fractions can be can befurther separated, e.g., by analytical gas-liquid chromatography (GLC)and analyzed, e.g., by GLC, IR, MS and/or NMR.

Typical reactions for fluorination by tetrafluorocobaltate(III) and/orcobalt trifluoride are described, e.g., in Burdon, et al., Journal ofFluorine Chemistry (1991), 51(2), 179-96. For fluorination by PotassiumTetrafluorocobaltate(III) a tetrahydrofuran is passed through a standardstirred reactor (1.2m×15 cm i.d.; 6 Kg KCoF₄) at 200° C., during 3hours. The reactor is purged with nitrogen (15 liters per hour for 1.5h), and the trap contents are washed with water. The dried crude productcan be analyzed, e.g., by GLC, IR, MS and/or NMR. For fluorination bycobalt trifluoride, crude product is passed via a liquid seal into asimilar reactor (1.3m×18 cm i.d.; packed with 10 Kg of CoF₃) during 3 h.Temperatures are maintained in the range of about 120-150° C. Followinga nitrogen sweep (25 liters per hour for 2 h) the contents of the coldtrap (−78° C.) are poured onto ice and washed with water. The combinedproducts are washed (aqueous sodium bicarbonate then water) and dried(MgSO₄ then P₂O₅). A part can be fractionally distilled through a 1 mvacuum jacketed spinning band column, with analysis by GLC. Fractionsobtained can be further separated by preparative GLC (e.g., Pye Series104 machine, with a flame-ionization detector; tube packings, Ucon L.B.550X on Chromasorb P 30-60 (1:4); analysis tube, 1.7m×4 mm i.d.;semi-preparative tube, 9.1m×7 mm i.d.) to give a pure sample of eachproduct. As appropriate or desired, the fluorinated products can beisomerized. The apparatus used for isomerization can be anelectrically-heated hard glass tube (320 mm×25 mm i.d.), packed with a1:1 mixture of aluminium fluoride and small glass spheres. Before use,this is heated to 280° C. for 24 h, whilst a slow stream of nitrogen ispassed through. With the tube temperature at 420° C., the fluorinatedproduct is passed through during 30 min. in a stream of nitrogen.Isomerized and non-isomerized products can be further separated, e.g.,by analytical gas-liquid chromatography (GLC) and analyzed, e.g., byGLC, IR, MS and/or NMR.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1-22. (canceled)
 23. A method of inducing anesthesia in a subject,comprising administering to the subject via the respiratory system aneffective amount of a compound or a mixture of compounds of Formula VI:

wherein: R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ independently are selectedfrom H, X, CX₃, CHX₂, CH₂X and C₂X₅; and wherein X is a halogen, thecompound has a vapor pressure of at least 0.1 atmospheres (76 mmHg) at25° C., and the number of hydrogen atoms of Formula VI do not exceed thenumber of carbon atoms, thereby inducing anesthesia in the subject. 24.The method of claim 23, wherein X is a halogen selected from the groupconsisting of F, Cl, Br and I.
 25. The method of claim 24, wherein X isF.
 26. The method of claim 23, wherein the compound is selected from thegroup consisting of: a) Furan,2,3,4,4-tetrafluorotetrahydro-2,3-bis(trifluoromethyl)- (CAS#634191-25-6); b) Furan,2,2,3,3,4,4,5-heptafluorotetrahydro-5-(trifluoromethyl)- (CAS#377-83-3); c) Furan,2,2,3,3,4,5,5-heptafluorotetrahydro-4-(trifluoromethyl)- (CAS#374-53-8); d) Furan,2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-, (2a,3β,4a)- (9CI)(CAS #133618-53-8); e) Furan,2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-, (2a,3a,4β)- (CAS#133618-52-7); f) Furan,2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-, (2α,3β,4α)- (9CI)(CAS #133618-53-8); g) Furan,2,2,3,4,5-pentafluorotetrahydro-5-(trifluoromethyl)-, (2α,3α,4β)- (9CI)(CAS #133618-52-7); h) Furan,2,2,3,3,5,5-hexafluorotetrahydro-4-(trifluoromethyl)- (CAS #61340-70-3);i) Furan, 2,3-difluorotetrahydro-2,3-bis(trifluoromethyl)- (CAS#634191-26-7); j) Furan, 2-chloro-2,3,3,4,4,5,5-heptafluorotetrahydro-(CAS #1026470-51-8); k) Furan,2,2,3,3,4,4,5-heptafluorotetrahydro-5-methyl- (CAS #179017-83-5); l)Furan, 2,2,3,3,4,5-hexafluorotetrahydro-5-(trifluoromethyl)-, trans-(9CI) (CAS #133618-59-4); and m) Furan,2,2,3,3,4,5-hexafluorotetrahydro-5-(trifluoromethyl)-, cis- (9CI) (CAS#133618-49-2).
 27. A method of inducing anesthesia in a subject,comprising administering to the subject via the respiratory system aneffective amount of a compound or a mixture of compounds of Formula VII:

wherein: R¹, R², R³, R⁴, R⁵, R⁶, R⁷, le, R⁹ and R¹⁻° independently areselected from H, X, CX₃, CHX₂, CH₂X, and C₂X₅; and wherein X is ahalogen, the compound has a vapor pressure of at least 0.1 atmospheres(76 mmHg) at 25° C., and the number of hydrogen atoms of Formula VII donot exceed the number of carbon atoms, thereby inducing anesthesia inthe subject.
 28. The method of claim 27, wherein X is a halogen selectedfrom the group consisting of F, Cl, Br and I.
 29. The method of claim28, wherein X is F.
 30. The method of claim 27, wherein the compound isselected from the group consisting of: a) 2H-Pyran,2,2,3,3,4,5,5,6,6-nonafluorotetrahydro-4- (CAS #71546-79-7); b)2H-Pyran, 2,2,3,3,4,4,5,5,6-nonafluorotetrahydro-6-(trifluoromethyl)-(CAS #356-47-8); c) 2H-Pyran,2,2,3,3,4,4,5,6,6-nonafluorotetrahydro-5-(trifluoromethyl)- (CAS#61340-74-7); d) 2H-Pyran,2,2,6,6-tetrafluorotetrahydro-4-(trifluoromethyl)- (CAS #657-48-7); e)2H-Pyran, 2,2,3,3,4,4,5,5,6-nonafluorotetrahydro-6-methyl- (CAS#874634-55-6); f) Perfluorotetrahydropyran (CAS #355-79-3); g) 2H-Pyran,2,2,3,3,4,5,5,6-octafluorotetrahydro-, (4R,6S)-rel- (CAS #362631-93-4);and h) 2H-Pyran, 2,2,3,3,4,4,5,5,6-nonafluorotetrahydro- (CAS#65601-69-6). 31-53. (canceled)